Autophagy [JOURNAL]
Sun
200 papers
FKBP8 inhibits influenza a virus infection by degrading viral M2 protein in lysosomes.
Lv L, Wang Q, Chen H … +7 more , Yang X, Zeng S, Zhang Z, Dorf ME, Li S, Pan J, Fu B
Autophagy · 2026 Jun · PMID 42212595 · Publisher ↗
Influenza A virus (IAV) remains a major threat to global public health, causing seasonal epidemics and occasional pandemics with significant morbidity and mortality. M2 (matrix protein 2), a key IAV envelope protein with...
Influenza A virus (IAV) remains a major threat to global public health, causing seasonal epidemics and occasional pandemics with significant morbidity and mortality. M2 (matrix protein 2), a key IAV envelope protein with ion channel activity, is critical for viral uncoating, genome release, and virion assembly. Here, we identified FKBP8 (FK506 binding protein 8) as a host restriction factor targeting IAV. Overexpression of FKBP8 inhibited IAV replication, while knockdown/knockout enhanced viral susceptibility. Mechanistically, FKBP8 interacted with M2 from diverse IAV strains via high-affinity binding between its tetratricopeptide repeat (TPR) domain and the LC3-interacting region (LIR) of M2, inhibiting viral entry. Importantly, FKBP8 mediated M2 degradation through the lysosomal pathway, not via translational inhibition, as shown by cycloheximide and lysosomal inhibitor (BafA1 and CQ) experiments. FKBP8 recruited RAB7A and LAMP1 to form a FKBP8-RAB7A-LAMP1-M2 complex, facilitating M2 transport to lysosomes. Additionally, FKBP8 interacted with envelope proteins of other enveloped RNA viruses, suggesting broad-spectrum antiviral potential. Our findings reveal FKBP8 as a conserved IAV restriction factor and its mechanism, providing insights for antiviral drug development. AA: amino acids; AP-MS: affinity tag purification-mass spectrometry; BCL2: B cell leukemia/lymphoma 2; BafA1: bafilomycin A; MbFKBP8: FK506 binding protein 8; CHX: cycloheximide; CQ: chloroquine; CTD: cytoplasmic tail domain; ED: ectodomain; EV: empty vector; FKBP8: FK506 binding protein 8; FL: full length; HCIPs: high-confidence interacting proteins; HsFKBP8: FKBP prolyl isomerase 8; IAV: influenza A virus; LIR: LC3-interacting region; LAMP1: lysosomal-associated membrane protein 1; M2: matrix protein 2; MOI: multiplicity of infection; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MmFKBP8: FK506 binding protein 8; NP: nucleoprotein; PA: polymerase acidic; PB1: polymerase basic 1; PB2: polymerase basic 2; PPIase: peptidyl-prolyl cis-trans isomerase; KO: knockout; RdRps: RNA-dependent RNA polymerases; RAB7A: RAB7, member RAS oncogene family; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TRIM41: tripartite motif-containing 41; TMD: transmembrane domain; vRNP: viral ribonucleoprotein.
MEN1/menin deficiency suppresses hepatocellular carcinogenesis via disrupting mitophagy-mediated mitochondrial homeostasis.
Chen C, Yu D, Tang D … +14 more , Liu M, Zhu J, Wang X, Dan G, Chen L, Tang S, Tian Q, Wang H, Meng F, Zhang T, Guo B, Chen T, Li H, Jin B
Autophagy · 2026 Jun · PMID 42210578 · Publisher ↗
Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with complex pathogenesis intertwined with metabolic and mitochondrial dysfunction. MEN1/menin is a protein with context-dependent functions in liver disease...
Hepatocellular carcinoma (HCC) is a highly lethal liver cancer with complex pathogenesis intertwined with metabolic and mitochondrial dysfunction. MEN1/menin is a protein with context-dependent functions in liver diseases. While MEN1 has been linked to HCC progression and mitochondrial homeostasis, its precise regulatory mechanism in these processes remains incompletely understood. Here, we report that MEN1 localizes to the outer mitochondrial membrane (OMM) in HCC cells, which is mediated by its N-terminal mitochondrial targeting sequence and the TOMM20 translocase complex. In a genetically engineered DEN- and CCl-induced HCC mouse model, hepatocyte-specific deficiency significantly suppressed tumorigenesis, a phenotype associated with impaired mitochondrial homeostasis. Mechanistically, deficiency disrupted mitochondrial function by manifesting as promoted mitochondrial fission, impaired oxidative phosphorylation, reduced ATP levels, and elevated reactive oxygen species during energy stress. Critically, loss inhibited mitophagy via downregulating the PINK1-PRKN/Parkin pathway, which impaired clearance of dysfunctional mitochondria and promotes their cytotoxic accumulation. Moreover, expression was upregulated in human HCC tissues, correlated with poor clinical outcomes and was positively associated with autophagy signatures. Notably, pharmacological activation of mitophagy reversed the tumor-suppressive effects of deficiency and . These findings identified a noncanonical role of mitochondrial MEN1 in driving HCC progression via regulating mitophagy homeostasis, and highlight the -mitophagy axis as a potential therapeutic target for HCC.: : albumin promoter-driven recombinase Cre; Baf A1: bafilomycin A; CCCP: carbonyl cyanide m-chlorophenyl hydrazone; CCl: carbon tetrachloride; Co-IP: co-immunoprecipitation; CQ: chloroquine; DEN: diethylnitrosamine; DNM1L: dynamin 1 like; DQ-BSA: self-quenched BODIPY-conjugated bovine serum albumin; Gal: galactose; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; HCC: hepatocellular carcinoma; WT: wild type; HMKO: hepatocyte-specific knockout; IF: immunofluorescence; IHC: immunohistochemistry; IMM: inner mitochondrial membrane; KEGG: Kyoto Encyclopedia of Genes and Genomes; MEFs: mouse embryonic fibroblasts; MEN1-FL: full-length MEN1; MFF: mitochondrial fission factor; MFN1: mitofusin 1; MTS: mitochondrial targeting sequence; OCR: oxygen consumption rate; OMM: outer mitochondrial membrane; OXPHOS: oxidative phosphorylation; PINK1: PTEN induced kinase1; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKN: parkin RBR E3 ubiquitin protein ligase; qPCR: RNA extraction and quantitative polymerase chain reaction; RNA-seq: RNA-sequencing; ROS: reactive oxygen species; sh: small hairpin RNA-mediated knockdown; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TOMM20: translocase of outer mitochondrial membrane 20.
PRRSV NSP2 hijacks host lipophagy via a LIPE-PNPLA2-AMPK-MTOR axis to promote viral replication.
Zhu Z, Lin Q, Zhang X … +5 more , Zhang M, Yan Y, Wang W, Wen W, Li X
Autophagy · 2026 May · PMID 42200529 · Publisher ↗
Porcine reproductive and respiratory syndrome virus (PRRSV) exploits host lipid metabolism to support its replication by harnessing lipids and their metabolic derivatives. Lipophagy, a selective autophagic process respon...
Porcine reproductive and respiratory syndrome virus (PRRSV) exploits host lipid metabolism to support its replication by harnessing lipids and their metabolic derivatives. Lipophagy, a selective autophagic process responsible for lipid droplet (LD) degradation and cellular lipid homeostasis regulation, has been implicated in viral infections, however, its specific role in PRRSV replication has not been investigated. In this study, we found that PRRSV infection triggered lipophagy, resulting in LD depletion and elevated intracellular free fatty acids. Mechanistically, the viral protein NSP2 was essential for PRRSV-induced lipophagy by directly interacting with LD-associated lipases LIPE and PNPLA2, facilitating their binding to MAP1LC3/LC3 via LIR motifs. Both interactions were required for lipophagy-dependent viral replication. Furthermore, we demonstrated that the AMPK signaling pathway critically regulated PRRSV-induced lipophagy. AMPK activation promoted viral replication, whereas its inhibition impaired both lipophagy and viral propagation. Conversely, MTOR signaling acted as a negative regulator of lipophagy, with MTOR inhibition promoting this process. Collectively, these findings established that PRRSV hijacked host lipophagy to facilitate viral replication through NSP2-LIPE-PNPLA2 interactions and an AMPK-MTOR signaling pathway. Our work provided mechanistic insights into viral pathogenesis and highlighted potential therapeutic targets for PRRSV prevention and control.: AMPK: AMP-activated protein kinase; co-IP: co-immunoprecipitation; CQ: chloroquine; CMA: chaperone-mediated autophagy; FFA: free fatty acid; HEK-293T: human embryonic kidney 293T; hpi: hour post infection; LAMP1: lysosome associated membrane protein 1; LD: lipid droplet; LIPA/LAL: lipase A, lysosomal acid type; LIPE/HSL: lipase E, hormone sensitive type; LIRs: LC3-interacting regions; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MGLL: monoglyceride lipase; MG132: carbobenzoxyl-l-leucyl-l-leucyl-l-leucinal; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; NSPs: non-structural proteins; ORFs: open reading frames; PNPLA2/ATGL: patatin-like domain 2, triacylglycerol lipase; PRRSV: porcine reproductive and respiratory syndrome virus; SQSTM1/p62: sequestosome 1.
Exercise hormone irisin alleviates rheumatoid arthritis by removing dysfunctional mitochondria.
Wu Y, Fu T, Teng Y … +4 more , Pan Y, Li L, Feng Y, Lin J
Autophagy · 2026 Jun · PMID 42186185 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Numerous clinical studies have revealed that exercise is extremely b...
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Numerous clinical studies have revealed that exercise is extremely beneficial for the outcome of RA. However, the underlying mechanism remains poorly understood. In the present study, we investigated the therapeutic efficacy of irisin, an exercise hormone, on K/BxN serum and collagen-induced arthritis (CIA), two well established mouse models for RA research. Mechanistically, irisin interacted with ITGAV (integrin subunit alpha V) and ITGB5 (integrin subunit beta 5) to activate mitophagy and remove leaked mitochondrial DNA (mtDNA) and reactive oxygen species (ROS), which suppressed the activation of NLRP3 (NLR family pyrin domain containing 3) inflammasome and then hindered the pathological process of experimental arthritis. Notably, the beneficial effects of irisin on the treatment of experimental arthritis were significantly abolished in mice with (autophagy related 5) conditional knockout in myeloid cells (). Our study elucidated the underlying mechanism through which exercise alleviated experimental arthritis and offered a feasible therapeutic strategy for RA. 3-MA: 3-methyladenine Ac-TUBA: acetylated TUBA; ACP5: acid phosphatase 5, tartrate resistant; AIM2: absent in melanoma 2; ANOVA: analysis of variance; ATP: adenosine triphosphate; BAF: bafilomycin A; BV:TV: bone volume per total volume; BMD: bone mineral density; BMDMs: bone marrow-derived macrophages; CASP1: caspase 1; CTSB: cathepsin B; CIA: collagen-indcued arthritis; DNM1L: dynamin 1 like; CYCS: cytochrome c, somatic; EtBr: ethidium bromide; FNDC5: fibronectin type III domain containing 5; FL-GSDMD: GSDMD full length; GSDMD: gasdermin D; HE: hematoxylin and eosin; iBMDMs: immortalized bone marrow-derived macrophages; IL1B: interleukin 1 beta; IL6: interleukin 6; IL18: interleukin 18; LDH: lactate dehydrogenase; LPS: lipopolysaccharide; MAP1LC3: microtubule associated protein 1 light chain 3; MSU: monosodium urate; mtROS: mitochondrial reactive oxygen species; mtDNA: mitochondrial DNA; NLRC4: NLR family CARD domain containing 4; NLRP1: NLR family pyrin domain containing 1; NLRP3: NLR family pyrin domain containing 3; NT-GSDMD: GSDMD N-terminal fragment; NAC: N-acetylcysteine; ox-mtDNA: oxidized mitochondrial DNA; PYCARD: PYD and CARD domain containing; PRKAA: protein kinase AMP-activated catalytic subunit alpha 1; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RA: rheumatoid arthritis; ROS: reactive oxygen species; SD: standard deviation; SiO: silicon dioxide; SQSTM1: sequestosome 1; Tb.Th: trabecular thickness; Tb.N: trabecular number; Tp.Sp: trabecular separation; TNF/TNF-α: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20; TUBA: tubulin alpha; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.
CHCHD2 and CHCHD10 promoted autophagic clearance of protein aggregates via GABARAPs.
Zhou W, Zhang MM, Tang W … +13 more , Singh BK, Zhang Z, Zhou L, Goh JKW, Tan FRE, Huang J, Sun Q, Xiao B, Priyanka G, Sun AX, Zeng L, Shen HM, Tan EK
Autophagy · 2026 Jul · PMID 42183628 · Publisher ↗
Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHC...
Mutations in mitochondrial protein CHCHD2 and its paralog CHCHD10 were identified in patients with Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) or Alzheimer disease (AD). CHCHD2 and CHCHD10 mutations caused neurodegeneration in model animals as seen in patients, but their pathophysiological roles remain elusive. Here we reported a direct role of CHCHD2 and CHCHD10 in autophagy. We identified a protein complex composing of CHCHD2-CHCHD10-C1QBP/p32-Atg8-family proteins (ATG8s), in which each molecule interacted with another. CHCHD2, CHCHD10 and C1QBP/p32 associated with ATG8s, preferentially, GABARAPs. Disease-associated CHCHD2 and CHCHD10 mutations exhibited varied interaction with ATG8s. By binding to GABARAPs, CHCHD2 and CHCHD10 underwent autophagic degradation, and recruited the ULK1 complex. Autophagy initiation defects occurred upon transient knockdown of , and also in human iPSC-derived or dopaminergic neurons. Importantly, CHCHD2 and CHCHD10 promoted autophagy. CHCHD2 reduced protein aggregates in cells and toxic SNCA/α-synuclein species in mouse striatum. Our study thus revealed mitochondrial proteins CHCHD2 and CHCHD10 as both autophagy substrates and autophagy activators and laid groundwork for therapy targeting patients with neurodegeneration.: AA: amino acid; AD: Alzheimer disease; ALS: amyotrophic lateral sclerosis; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG8: mammalian Atg8-family protein; ATG13: autophagy related 13; bafA1: bafilomycin A; C1QBPp32/gC1qRHABP1: complement component 1, q subcomponent binding protein; CHCHD2/MNRR1/MIX17B: coiled-coil-helix-coiled-coil-helix domain containing 2; CHCHD10/MIX17A: coiled-coil-helix-coiled-coil-helix domain containing 10; CHX: cycloheximide; CMA: chaperone-mediated autophagy; CRISPR: clustered regularly interspaced short palindromic repeats; CQ, chloroquine; DA: dopaminergic; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; RB1CC1/FIP200: RB1 inducible coiled-coil 1; FTD: frontotemporal dementia; GABARAP: gamma-aminobutyric acid receptorbassociated protein; GABARAPL1: GABA type A receptor associated protein like 1; GABARAPL2: GABA type A receptor associated protein like 2; hESC: human embryonic stem cells; iPSC: induced pluripotent stem cell; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; LAMP2A: lysosomal-associated membrane protein 2A; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LIR: LC3-interacting region; PD: Parkinson disease; SQSTM1/p62: sequestosome 1; TARDBP/TDP-43: TAR DNA binding protein; TH: tyrosine hydroxylase; TMR, tetramethylrhodamine; WT: wild type; UB: ubiquitin; ULK1: unc-51 like kinase 1.
Mammalian lysophagy: mechanisms and pathophysiological implications.
Ji F, Dai M, Wang Z … +7 more , Dai E, Kang R, Klionsky DJ, Tang D, Huang Y, Sun Y, Liu T
Autophagy · 2026 Jun · PMID 42183611 · Publisher ↗
Lysophagy is a form of selective macroautophagy/autophagy that preserves lysosomal integrity by eliminating damaged lysosomes. Lysosomal membrane permeabilization can arise from diverse physiological and pathological ins...
Lysophagy is a form of selective macroautophagy/autophagy that preserves lysosomal integrity by eliminating damaged lysosomes. Lysosomal membrane permeabilization can arise from diverse physiological and pathological insults, including proteotoxic stress, crystalline particles, pathogens and chemical perturbations, and occurs along a continuum ranging from transient nanoscale lesions to catastrophic rupture. Cells respond to lysosomal injury through a hierarchical quality-control network in which membrane repair, lysophagic removal and lysosomal regeneration operate in a coordinated manner. Damage recognition involves sensing of exposed lumenal glycans and membrane lipids, followed by ubiquitin-dependent tagging that recruits selective autophagy receptors and activates the core autophagy machinery to form lysophagosomes. Lysophagy is closely integrated with membrane repair pathways, metabolic signaling and innate immune responses that together determine lysosomal fate. Dysregulated lysosomal quality control has been implicated in diverse diseases, including neurodegeneration, infection, cancer and chronic inflammatory disorders. In this review, we summarize current mechanistic insights and emerging experimental approaches for studying lysosomal quality control and lysophagy in mammalian cells. ALR, autophagic lysosome reformation; ALS, amyotrophic lateral sclerosis; ATG8, mammalian Atg8-family protein; ER, endoplasmic reticulum; ESCRT, endosomal sorting complexes required for transport; LAMPs, lysosome associated membrane proteins; LIR, LC3-interacting region; LLOMe, L-leucyl-L-leucine methyl ester; LMP, lysosomal membrane permeabilization; PITT, phosphoinositide-initiated membrane tethering and lipid transport; PtdIns3K, class III phosphatidylinositol 3-kinase; PtdIns3P, phosphatidylinositol-3-phosphate; PtdIns4P, phosphatidylinositol-4-phosphate; ROS, reactive oxygen species; V-ATPase, vacuolar-type H -ATPase.
NMN/NAD enhances SIRT2-modulated microtubule dynamics to improve mitochondrial and mitophagy functions in senescent cells.
Cui J, Ren S, Wang B … +10 more , Zhang N, Zhu S, Zhang Y, Qi X, Meng W, Shao L, Gao S, Xing L, Li Z, Mu X
Autophagy · 2026 May · PMID 42178923 · Publisher ↗
The effect of NAD in enhancing mitochondrial function and energy metabolism in human cells is closely linked to NAD-dependent sirtuins (i.e. SIRT1 and SIRT3). SIRT2 primarily functions in the cytoplasm, where it can serv...
The effect of NAD in enhancing mitochondrial function and energy metabolism in human cells is closely linked to NAD-dependent sirtuins (i.e. SIRT1 and SIRT3). SIRT2 primarily functions in the cytoplasm, where it can serve as a key deacetylase for tubulin and modulates stability of microtubules. Microtubule plays a pivotal role in regulating mitochondrial dynamics, including mitochondrial movement, fission/fusion, repair, and mitophagy-dependent clearance. However, the potential role of NAD in modulating SIRT2-related microtubule stability, and the potential involvement of the NAD-SIRT2-microtubule axis in regulating mitochondrial and mitophagy functions remains unexplored. In this study, we demonstrate that senescent muscle cells exhibit microtubule hyper-stabilization and reduced dynamics, concomitant with SIRT2 inactivation and tubulin hyperacetylation. These alterations impair microtubule-dependent mitochondrial repair and mitophagy function, resulting in mtDNA leakage, CGAS-STING1 activation and subsequently accelerated senescence. Notably, treatment with nicotinamide mononucleotide (NMN) effectively reactivates SIRT2, restores microtubule dynamics, and enhances mitochondrial quality control by promoting repair and mitophagy. Consequently, NMN mitigates CGAS-STING1-driven senescence. Our findings reveal a novel mechanism by which NMN preserves mitochondrial health in senescent cells via a SIRT2-microtubule axis, highlighting its protective role beyond canonical NAD-sirtuin pathways, and suggesting microtubule dynamics as a promising therapeutic target for improving cellular defects associated with mitochondrial and mitophagy dysfunctions.: D-gal: D-galactose; EdU: 5-ethynyl-20-deoxyuridine; HDAC6: histone deacetylase 6; LAMP1: lysosome associated membrane protein 1; MSCs: mesenchymal stem/stromal cells; mtDNA: mitochondrial DNA; NAD: nicotinamide adenine dinucleotide; NMN: nicotinamide mononucleotide; PBS: phosphate-buffered saline; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SIRT2: sirtuin 2.
Membrane ATG8ylation in secretory autophagy.
Debnath J, Leidal AM
Autophagy · 2026 May · PMID 42178909 · Publisher ↗
Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion....
Mammalian Atg8-family (ATG8) proteins are crucial for macroautophagic/autophagic degradation in the lysosome and facilitate non-degradative processes including multiple distinct forms of unconventional protein secretion. These secretion pathways, collectively termed secretory autophagy, depend upon ATG8 conjugated to membranes to both specify and traffic molecules for extracellular release. Here, we review the current understanding of how membrane ATG8ylation supports secretory autophagy, and propose a cell biological framework for classifying the growing repertoire of secretory autophagy pathways based on membrane ATG8ylation at discrete intracellular vesicular intermediates. Finally, we detail the emerging roles of these pathways in physiology and disease.: Aβ, amyloid-β; Acb1, acyl-coA-binding 1; ALS, amyotrophic lateral sclerosis; APP, amyloid beta precursor protein; APEX2, ascorbate peroxidase; ATG, autophagy related; AWOL, autophagosome-mediated exit without lysis; BafA1, bafilomycin A; BirA*, mutant BirA biotin ligase; BMI, body-mass index; CASM, ATG8 conjugation at single membranes; DAMPs, danger/damage-associated molecular patterns; DBI, diazepam binding inhibitor, acyl-CoA binding protein; DSS, dextran sodium sulfate; ER, endoplasmic reticulum; ERGIC, endoplasmic reticulum intermediate compartment; ESCRT, endosomal complexes required for transport; EVs, extracellular vesicles; EVPs, extracellular vesicles and particles; HMGB1, high mobility group box 1; IDE, insulin degrading enzyme; IFNB, interferon beta; ILV, intralumenal vesicles; LANDO, LC3-associated endocytosis; LAP, LC3-associated phagocytosis; LIR, LC3 interacting region; LDELS, LC3-dependent EV loading and secretion; LLOMe, L-leucyl-L-leucine methyl ester hydrobromide; M2, influenza A virus matrix 2, MAD, migratory autolysosome disposal; miRNAs, microRNAs; M-MDSC, monocytic myeloid derived suppressor cells; MVEs, multivesicular endosomes; PAMPs, pathogen-associated molecular patterns; P-bodies, processing bodies; PE, phosphatidylethanolamine; PD, Parkinson disease; PS, phosphatidylserine; RBPs, RNA binding proteins; R-EV, RAB22A-induced extracellular vesicle; SLC2A1, solute carrier family 2 member 1; TFRC, transferrin receptor; TGN, trans-Golgi network; TMED10, transmembrane p24 trafficking protein 10; THU, TMED10-channeled unconventional secretion; SALI, secretory autophagy during lysosome inhibition; SCF, SKP1-CUL1-F-box; SNAREs, soluble NSF attachment protein receptors.
ATG5 in DCs attenuates anti-malarial cellular immune responses through interfering with TLR2-mediated CD209A/DC-SIGN expression.
Fan Y, Jiao S, Li H … +6 more , Gao Y, Fang J, Zhang K, Guo S, Xu W, Liu T
Autophagy · 2026 May · PMID 42171217 · Publisher ↗
It is well established that the function of DCs (dendritic cells) is impaired during malaria infection; however, the underlying mechanisms responsible for this impairment remain poorly understood. In this study, we found...
It is well established that the function of DCs (dendritic cells) is impaired during malaria infection; however, the underlying mechanisms responsible for this impairment remain poorly understood. In this study, we found that ATG5 (autophagy related 5) deficiency in DCs significantly suppressed the growth of malaria blood-stage parasites, and this effect was independent of both canonical and non-canonical macroautophagy/autophagy pathways in these cells. The reduced parasite growth observed in mice was associated with an enhanced parasite-specific CD4 T cell response, which provided crucial support for the functional activation of Plasmodium-specific CD8 T cells. Mechanistically, ATG5 deficiency led to a marked increase in the expression of the phagocytic receptor CD209A/DC-SIGN on conventional DCs (cDCs), thereby enhancing their capacity to activate Plasmodium-specific CD4 T cell responses. Furthermore, the expression of CD209A was mediated by the TLR2 (toll-like receptor 2) signaling pathway, which was significantly augmented in the absence of ATG5. Thus, we reveal a novel role for ATG5 in modulating anti-malarial cellular immune responses by influencing TLR2-mediated CD209A expression in cDCs. These findings not only enhance our understanding of impaired DC function during malaria infection but also provide valuable insights for the design of more effective malaria vaccines. ATG5: autophagy related 5; cDCs: conventional dendritic cells; CFSE: carboxyfluorescein succinimidyl ester; DC-SIGN: dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin; IFNG/IFN-γ: interferon gamma; LAP: LC3-associated phagocytosis; MAPK: mitogen-activated protein kinase; NFKB1/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105; pRBCs: parasitized red blood cells; PRRs: pattern recognition receptors; TLR2: toll-like receptor 2; TNF/TNF-α: tumor necrosis factor.
UCHL3 drives ferroptosis in nucleus pulposus cells by deubiquitinating HMGB1 to activate NCOA4-mediated ferritinophagy.
Hu T, Cui P, Zhao X … +13 more , Wang W, Ma Y, Hu X, Zhang H, Fan Z, Wang D, Huang Q, Pan F, Huang H, Cui C, Chen X, Rong Y, Lu S
Autophagy · 2026 May · PMID 42169250 · Publisher ↗
Ferroptosis contributes to intervertebral disc degeneration (IVDD), yet its upstream regulatory mechanisms in nucleus pulposus cells (NPCs) remain unclear. Here, we identify a novel UCHL3-HMGB1-NCOA4 signaling axis that...
Ferroptosis contributes to intervertebral disc degeneration (IVDD), yet its upstream regulatory mechanisms in nucleus pulposus cells (NPCs) remain unclear. Here, we identify a novel UCHL3-HMGB1-NCOA4 signaling axis that drives NPC ferroptosis. Transcriptomic and clinical analyses reveal that UCHL3 is upregulated in degenerative discs, with its expression correlating positively with both IVDD severity and ferroptosis markers. Mechanistically, UCHL3 deubiquitinates and stabilizes HMGB1 by cleaving Lys48-linked polyubiquitin chains, thereby promoting the accumulation of cytoplasmic HMGB1. This stabilized HMGB1 activates NCOA4-mediated ferritinophagy, initiating ferroptosis. Silencing or mitigates these effects. Furthermore, a polydopamine-based nanoplatform (PDA@si-) achieves dual therapeutic action, silencing while scavenging ROS and chelating iron, which effectively inhibits ferroptosis and alleviates IVDD in rats. These findings establish UCHL3 as a pivotal regulator of NPC ferroptosis and highlight PDA@si- as a promising therapeutic strategy for IVDD. AAV: adeno-associated virus; CCK-8: cell counting kit-8; Co-IP: co-immunoprecipitation; DUBs: deubiquitinating enzymes; ECM: extracellular matrix; GPX4: glutathione peroxidase 4; GSH: glutathione; HE: hematoxylin and eosin; HMGB1: high mobility group box 1; IF: immunofluorescence; IHC: immunohistochemistry; IP/MS: immunoprecipitation mass spectrometry; IVDD: intervertebral disc degeneration; IVDs: intervertebral discs; MRI: magnetic resonance imaging; NCOA4: nuclear receptor coactivator 4; NP: nucleus pulposus; NPCs: nucleus pulposus cells; PDA: polydopamine; PG: Pfirrmann grading; ROS: reactive oxygen species; siRNA: small interfering RNAs; SO-FG: Safranin O-Fast Green; TBHP: tert-butyl hydroperoxide; TEM: transmission electron microscope; UCHL3: ubiquitin C-terminal hydrolase L3; WT: wild-type.
High-fat diet exacerbates experimental colitis by inhibiting lysosomal function via the STAT3-TFEB Axis.
He H, Guo X, Xu M … +11 more , Tan Z, Tan C, Li X, Xiang Z, He P, Deng B, Pu Y, Liu Y, Zhang L, Zhang J, Dong W
Autophagy · 2026 May · PMID 42165414 · Publisher ↗
An elevated risk for inflammatory bowel disease (IBD) has been linked to the intake of high-fat diet (HFD), yet the underlying molecular mechanisms remain unclear. The lysosome and the macroautophagy/autophagy-lysosome p...
An elevated risk for inflammatory bowel disease (IBD) has been linked to the intake of high-fat diet (HFD), yet the underlying molecular mechanisms remain unclear. The lysosome and the macroautophagy/autophagy-lysosome pathway (ALP) are critical for maintaining the intestinal epithelial barrier. By employing both an in vivo model of dextran sulfate sodium (DSS)-induced colitis in mice and an in vitro model using lipopolysaccharide (LPS)-treated NCM460 cells, we established that HFD in vivo and palmitic acid (PA) in vitro profoundly impair epithelial barrier function and amplify inflammation, which was linked to the suppression of lysosomal function and the ALP. Mechanistically, HFD in vivo and PA in vitro activated STAT3 (p-STAT3[Y705]) under DSS- and LPS-associated inflammatory stress, respectively. This led to a dual suppression of TFEB: on the one hand, activated STAT3 directly bound to the promoter to inhibit its transcription; on the other hand, it facilitated the lysosomal recruitment of MTOR and activated MTORC1, which promoted TFEB phosphorylation (p-TFEB[S211]) and hindered its nuclear translocation. This cascade resulted in lysosomal membrane permeabilization (LMP), loss of acidification, and impaired degradative function. Intestinal epithelial-specific knockout of or pharmacological activation of TFEB restored lysosomal function, repaired the epithelial barrier, and ameliorated colitis. Conversely, rectal administration of AAV9- reversed the protective effects conferred by knockout. Our study reveals that HFD in vivo and PA in vitro disrupt lysosomal function and the intestinal barrier through the STAT3-TFEB axis, suggesting this signaling pathway as a promising avenue for intervention in diet-associated IBD.: AB-PAS: Alcian blue-periodic acid-Schiff; ALP: autophagy-lysosome pathway; CD: Crohn disease; ChIP: chromatin immunoprecipitation; CLEAR: coordinated lysosomal expression and regulation; DSS: dextran sulfate sodium; HFD: high-fat diet; IBD: inflammatory bowel disease; IF: immunofluorescence; IHC: immunohistochemistry; LAMP: lysosome associated membrane protein; LGALS3/Gal3: galectin 3; LMP: lysosomal membrane permeabilization; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1; PA: palmitic acid; RRAG: Ras-related GTP binding; RRAG-CA: constitutively active RRAG GTPase; RT-qPCR: reverse transcription quantitative PCR; SQSTM1/p62: sequestosome 1; STAT3: signal transducer and activator of transcription 3; TA1: TFEB activator 1; TEM: transmission electron microscopy; TFEB: transcription factor EB; TJ: tight junction; TUNEL: terminal deoxynucleotidyl transferase dUTP nick-end labeling; UC: ulcerative colitis; WB: western blot; WT: wild-type.
Cytosolic DNA as an inhibitor of rDNA transcription.
Xu Y, Lu S, Wan W
Autophagy · 2026 May · PMID 42165388 · Publisher ↗
Cytosolic DNA is well established as an inducer of innate immunity through activating DNA-sensing machinery, such as the CGAS-STING1 pathway. Recently, we uncovered a previously unknown function of cytosolic DNA by eluci...
Cytosolic DNA is well established as an inducer of innate immunity through activating DNA-sensing machinery, such as the CGAS-STING1 pathway. Recently, we uncovered a previously unknown function of cytosolic DNA by elucidating its role in regulation of rDNA transcription. Cytosolic DNA interacts with UBTF and POLR1A, two essential components of the RNA polymerase I transcription machinery, thereby retaining a portion of these two proteins in the cytoplasm and resulting in an inhibition of rDNA transcription. This leads to decreased protein synthesis and reduced cell proliferation. Furthermore, STING1-induced autophagy selectively eliminates cytosolic DNA, abolishing the cytoplasmic retention of UBTF and POLR1A and consequently restoring rDNA transcription, protein synthesis, and cell proliferation. Thus, our findings reveal a DNA-sensing pathway-independent function of cytosolic DNA, which underscores cytosolic DNA as a novel player in cell metabolism.: cGAMP: cyclic GMP-AMP; CGAS: cyclic GMP-AMP synthase; HSV-1: herpes simplex virus-1; POLR1A: RNA polymerase I subunit A; rDNA: ribosomal DNA; rRNA: ribosomal RNA; SQSTM1: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; UBTF: upstream binding transcription factor.
A Rosella-PLIN2 knock-in mouse reveals lipophagy and immunometabolic interplay in atherosclerosis.
Laval T, Joyce N, Boucher DM … +13 more , Labrana H, Rochon V, Emerton C, Dharia M, Robichaud S, Lorant V, Nguyen MA, Geoffrion M, Rayner KJ, Gibbings D, Nutter LMJ, Russell RC, Ouimet M
Autophagy · 2026 Jun · PMID 42163465 · Publisher ↗
Cytosolic lipid droplets (LDs) regulate lipid homeostasis, with abnormal LD dynamics linked to metabolic diseases like atherosclerosis. In macrophage foam cells, LDs undergo autophagic degradation via lipophagy, but the...
Cytosolic lipid droplets (LDs) regulate lipid homeostasis, with abnormal LD dynamics linked to metabolic diseases like atherosclerosis. In macrophage foam cells, LDs undergo autophagic degradation via lipophagy, but the extent of this process in vascular smooth muscle cell (VSMC) foam cells remains unclear. To track lipophagy in real time, we developed a Rosella-PLIN2 (perilipin 2) biosensor by tagging PLIN2 with the fluorescent pH-biosensor Rosella. We show that proatherogenic lipoproteins and autophagy activators stimulate lipophagy in human macrophages. Targeting LDs with an LC3 fusion protein or LD-autophagy tethering compounds (LD-ATTECs) selectively enhanced lipophagy, promoting foam cell LD clearance. In an atherosclerosis model, Rosella-PLIN2 accurately tracked lipophagy in arterial foam cells, revealing distinct PLIN2 expression patterns in macrophage and non-leukocyte foam cells. We identified a lipophagy deficiency in VSMC foam cells and demonstrate that enhancing lipophagy promotes LD catabolism in primary VSMC foam cells. TREM2 macrophages exhibited high lipid content and low lipophagy flux, whereas TREM2 macrophages had low lipid content and high lipophagy flux. Our findings highlight a cell-specific interplay between lipophagy and immunometabolism in arterial foam cells, unveiling novel therapeutic avenues for atherosclerosis. Additionally, the Rosella-PLIN2 model provides a powerful tool for studying LD metabolism, offering new insights into lipid homeostasis and disease mechanisms.: AgLDL: aggregated LDL; Baf-A1: bafilomycin A; BMDMs: bone marrow-derived macrophages; HDL: high-density lipoproteins; LD: lipid droplets; LD-ATTECs: LD-autophagy tethering compounds; LDL: low-density lipoproteins; LIPA/LAL: lysosomal acid lipase A; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; LTA: lipoteichoic acid; MFI: mean fluorescence intensity; OA: oleic acid; p-ATG16L1: phospho-ATG16L1; PLIN2: perilipin 2; PLINs: perilipins; RCT: reverse cholesterol transport; TLR: toll-like receptor; VSMCs: vascular smooth muscle cells; WSC: water-soluble cholesterol.
Iterative design leads to a smart probe capable of quantifying autophagic flux with switchable fluorescence via engaging MAP1LC3/LC3.
Lu Y, Wang N, Liu M … +6 more , Lu Z, Fan S, Lv W, Lu Y, Han F, Li X
Autophagy · 2026 May · PMID 42163447 · Publisher ↗
Tracking macroautophagic/autophagic flux in live cells is vital for understanding its pathophysiology; however, its dynamic nature complicates assay development. Although fluorescent protein-tagged markers and microenvir...
Tracking macroautophagic/autophagic flux in live cells is vital for understanding its pathophysiology; however, its dynamic nature complicates assay development. Although fluorescent protein-tagged markers and microenvironment-sensitive small-molecule fluorescent probes have been developed, non-transfection-based and highly specific assays remain underexplored. In this study, we present the design, synthesis, and application of an activity-based autophagy probe (ATP1) for dynamically quantifying autophagic flux. ATP1 was developed through an iterative, docking-guided design strategy to secure MAP1LC3/LC3 engagement, coupled with in-depth analysis of structure-fluorescence relationships to program dual smart-signal behaviors. It displays LC3-binding-triggered fluorogenic activation and autophagosome-lysosome fusion-triggered ratiometric changes. By engaging LC3, the probe is inherently specific to autophagy, and its dynamic signal enables real-time tracking of autophagic flux with high sensitivity. We demonstrate ATP1's exceptional performance in live cells and mice, with a dynamic signal paralleling the mRFP-GFP-LC3 assay. Notably, ATP1 provides significant benefits, including low background signals, compatibility with primary cells, and effectiveness in wild-type mice, where transfection-based assays are often impractical. Furthermore, the probe aids in the discovery of autophagy modulators. In conclusion, ATP1 offers a straightforward, specific, and non-transfection-based method for assessing autophagic flux, serving as a powerful tool for advancing autophagy research.: 3-MA: 3-methyladenine; ATP: autophagy probe; BafA1: bafilomycin A; CBF: cerebral blood flow; FP: fluorescent protein; HBMECs: human brain microvascular endothelial cells; HBSS: Hanks' balanced salt solution; HEPES: 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid; ITC: isothermal titration calorimetry; LIR: LC3-interacting region; LSCI: laser speckle contrast imaging; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; OGD: oxygen-glucose deprivation; PBS: phosphate-buffered saline; Rapa: rapamycin; Wort: wortmannin.
FGF21 rejuvenates aged human adipose-derived mesenchymal stem cells via enhancement of TFE3-mediated autophagy flux.
Song B, Liu C, Hu J … +9 more , Zhao X, Fan H, Liu T, Gao G, Zhang X, Guang X, Zhou Q, Wang K, Lu W
Autophagy · 2026 May · PMID 42157427 · Publisher ↗
Intracerebral hemorrhage (ICH) is a neurological disorder characterized by a high mortality rate for which there is currently no definitive cure. Research has demonstrated that adipose-derived mesenchymal stem cells (ASC...
Intracerebral hemorrhage (ICH) is a neurological disorder characterized by a high mortality rate for which there is currently no definitive cure. Research has demonstrated that adipose-derived mesenchymal stem cells (ASCs) exhibit considerable potential in treating ICH. However, the advanced age of ICH patients and the necessary cell expansion before transplantation therapy could result in the senescence of ASCs, thereby compromising their viability and therapeutic efficacy. This study aims to investigate whether FGF21 (fibroblast growth factor 21) can rejuvenate aged ASCs by enhancing macroautophagy/autophagy flux and subsequently enhance the therapeutic efficacy of ICH. We demonstrated that the autophagy flux of aged ASCs was significantly decreased and FGF21 treatment significantly reversed the senescence phenotype and increased the viability of aged ASCs. Mechanistically, our findings suggested that FGF21 rejuvenates aged ASCs by augmenting autophagy flux, a process partly mediated by TFE3 (transcription factor E3) nuclear translocation. The FGF21-induced TFE3 nuclear translocation was partially facilitated potentially via the FGFR1-SIRT1-MTOR pathway. In addition, FGF21 enhanced the potential of senescent ASCs to differentiate into neurons. In the in vivo study, we further verified that FGF21 could enhance the therapeutic effect of ASCs on acute ICH rats. In conclusion, these results indicated that FGF21 could restore ASC viability by upregulating TFE3-mediated autophagy flux in part through the FGFR1-SIRT1-MTOR signaling pathway, enhanced the potential to improve the differentiation of ASCs into neural stem cells and enhanced the therapeutic effect of ASCs transplantation in acute ICH.: FGF21: fibroblast growth factor 21; TFE3: transcription factor E3; TFEB: transcription factor EB; DMEM: Dulbecco's modified Eagle medium; RAPA: rapamycin; 3-MA: 3-methyladenine; CQ: chloroquine; DMSO: dimethyl sulfoxide; RT-qPCR: quantitative real-time PCR; pAb: polyclonal antibody; mAb: monoclonal antibody; LAMP1: lysosomal associated membrane protein 1; SQSTM1/p62: sequestosome 1; MAP1lc3/LC3: microtubule associated protein 1 light chain 3; GFAP: glial fibrillary acidic protein; MAP2: microtubule associated protein 2; SOX2: SRY-box transcription factor 2; MOI: multiplicity of infection; FGFR1: fibroblast growth factor receptor 1; SIRT1: sirtuin 1; MTOR: mechanistic target of rapamycin kinase; ROS: reactive oxygen species; siRNA: small interfering RNA; OD: optical density; SASP: senescence-related secretion phenotype; IL6: interleukin 6; IL1B/IL-1β: interleukin 1 beta; TNF/TNF-α: tumor necrosis factor; CCL2/MCP-1: C-C motif chemokine ligand 2; BDNF: brain derived neurotrophic factor; VEGF: vascular endothelial growth factor; ICH: intracerebral hemorrhage; MLPT: modified limb placement test.
Autophagy functions in lung macrophages and dendritic cells to regulate allergen-dependent inflammatory responses.
Dubey N, Woodson R, Hendrix SV … +10 more , Rosen AL, Kinsella RL, McKee SR, Starick M, Rivera-Espinal N, Naik SK, Smirnov A, Kreamalmeyer D, Kau AL, Stallings CL
Autophagy · 2026 May · PMID 42157421 · Publisher ↗
Asthma affects 260 million people worldwide, with severe asthma cases that are associated with T17 and T1 responses and neutrophil-dominated inflammation being the most difficult to treat due to corticosteroid insensitiv...
Asthma affects 260 million people worldwide, with severe asthma cases that are associated with T17 and T1 responses and neutrophil-dominated inflammation being the most difficult to treat due to corticosteroid insensitivity. Single nucleotide polymorphisms in the gene, which codes for a protein required for the cellular recycling process of macroautophagy/autophagy, are associated with higher risk for developing severe asthma. We explored the mechanistic basis for the genetic association of variants with severe asthma. We identified an autophagy-dependent role for ATG5 in lung macrophages and dendritic cells (DCs) for suppressing T17 responses and neutrophil accumulation in house dust mite (HDM)-challenged mice, a T17- and T1-dominated model for allergic airway inflammation due to contamination of the HDM with residual lipopolysaccharide. In contrast, autophagy was required to promote eosinophil accumulation in the T2-dominated ovalbumin model of allergic airway inflammation, supporting a model where autophagy functions in lung macrophages and DCs to suppress T17 responses and promote T2 responses in an allergen-dependent manner. In addition, we discover that autophagy is also required in macrophages exposed to HDM to suppress the secretion of cytokines and chemokines that would otherwise recruit neutrophils to the lungs, independent of T cell responses. Together, our data identify T-cell-dependent and -independent ways autophagy in innate immune cells suppresses the neutrophil accumulation in lungs that is associated with severe asthma.: AHR: airway hyperresponsiveness; BAL: bronchoalveolar lavages; BMDM: bone marrow-derived macrophages; CSF3/G-CSF: colony stimulating factor 3; DCs: dendritic cells; H&E: hematoxylin and eosin; HDM: house dust mites; i.n.: intranasal/intranasally; i.p.: intraperitoneal/intraperitoneally; Jax: The Jackson Laboratory; KC: keratinocyte-derived chemokine; LPS: lipopolysaccharide; MHC: major histocompatibility complex; OVA: ovalbumin; PAMPs: pathogen-associated molecular patterns; PAS: periodic acid-Schiff; SNP: single-nucleotide polymorphism.
A fetus with severe developmental defects caused by dominant-negative and hypomorphic alleles.
Carpentier M, Chatron N, Rouvet I … +6 more , Monin P, Nadaud B, Consortium A, Sanlaville D, Courchet J, Strappazzon F
Autophagy · 2026 May · PMID 42157368 · Publisher ↗
Macroautophagy/autophagy is a fundamental process for neuronal homeostasis, yet its role in human development, notably brain development, remains poorly understood. Here, we report a fetus presenting severe developmental...
Macroautophagy/autophagy is a fundamental process for neuronal homeostasis, yet its role in human development, notably brain development, remains poorly understood. Here, we report a fetus presenting severe developmental defects, including brain malformations, carrying two deleterious variants in , a gene associated with severe neurodevelopmental disorders: maternally inherited nonsense mutation Arg659Ter (hereafter R659*) and a missense mutation Arg481Gln (hereafter R481Q). Functional analyses showed ATG7 acting as a dominant-negative allele, whereas ATG7 was hypomorphic, revealing arginine 481 as a critical residue for ATG7-LC3 interaction in mammals. Loss of ATG7 function disrupted autophagosome formation, promoted abnormal axonal elongation and branching in neurons, and nearly abolished canonical autophagy in fetal cells. These findings highlight ATG7 as a key regulator of development and provide mechanistic insight into autophagy-related neurodevelopmental disorders.Abbreviations: ATG: autophagy related; CHX: cycloheximide; cHBSS: complete Hanks' buffered salt solution; C572A: Cys572Ala catalytically-inactive mutant; DIV: day in vitro; DMSO: dimethyl sulfoxide; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; MAP1LC3: microtubule associated protein 1 light chain 3; NDD: neurodevelopmental disorder; NMD: nonsense-mediated decay; PB: permeabilization buffer; PBS: phosphate-buffered saline; RT-PCR: reverse transcriptase polymerase chain reaction; R481Q: Arg481Gln; R659*: Arg659Ter; shRNA: short hairpin RNA; siRNA: small interfering RNA.
Mechanical stress-mediated ferritinophagy aggravates cartilage endplate degeneration via a PIEZO1-NCOA4-ZBP1 axis.
Wang W, Qian D, Sun S … +13 more , Yao Y, Yang X, Liu W, Song Z, Yu H, Hou L, Hou P, Wu J, Ma Z, Ma J, Hu F, Wang H, Zhang X
Autophagy · 2026 May · PMID 42153663 · Publisher ↗
Abnormal mechanical stress is closely linked to intervertebral disc degeneration (IVDD). Iron homeostasis disorder occurs in various degenerative diseases, including IVDD. PIEZO1 serves as a mechanosensitive cation chann...
Abnormal mechanical stress is closely linked to intervertebral disc degeneration (IVDD). Iron homeostasis disorder occurs in various degenerative diseases, including IVDD. PIEZO1 serves as a mechanosensitive cation channel, involving in multiple physiological and pathological processes; however, its potential association with iron homeostasis and IVDD remain to be elucidated. Here, it is discovered that PIEZO1 accumulates in cartilage endplate (CEP) during IVDD, accompanied by intensive ferritinophagy. Specific activation of PIEZO1 or NCOA4 (nuclear receptor coactivator 4) aggravates CEP degeneration. Conversely, chondrocyte-specific knockout of mitigates CEP degeneration by restoring the labile iron pool and stabilizing the mitochondrial genome. Mechanistically, PIEZO1-mediated nuclear translocation of YAP1 (Yes1 associated transcriptional regulator) enhances NCOA4-dependent ferritinophagy by promoting extracellular Ca influx under oxidative stress. Moreover, ferritinophagy induces in the accumulation and release of Z-form mitochondrial DNA (Z-mtDNA), resulting in the activation of ZBP1 (Z-DNA binding protein 1), ultimately leading to NFKB-dependent inflammatory cascade. Therapeutically, blocking PIEZO1-mediated calcium influx or suppressing YAP1 activation alleviates ferritinophagy. Additionally, silencing attenuates Z-mtDNA-ZBP1-NFKB axis-driven IVDD. Collectively, our findings suggest that mechanical overload induces ferritinophagy-dependent CEP degeneration via PIEZO1 activation and subsequent upregulation of the Z-mtDNA-ZBP1-NFKB axis, which might furnish a therapeutic target for IVDD.: AAV: adeno-associated virus; ALP: alkaline phosphatase; ARS: alizarin red S; BV:TV: bone volume:total volume; CAMK2/CaMKII: calcium/calmodulin dependent protein kinase II; CEP: cartilage endplate; CEPCs: cartilage endplate chondrocytes; ChIP: chromatin immunoprecipitation; CKO: conditional knockout; CsA: cyclosporin A; Co-IP: co-immunoprecipitation; DHI: disc height index; ECM: extracellular matrix; EtBr: ethidium bromide; HIF: hypoxia inducible factor; IVDD: intervertebral disc degeneration; KD: knockdown; LAT: large tumor suppressor kinase; LSI: lumbar spine instability; MDA: malondialdehyde; Mito-ROS: mitochondrial reactive oxygen species; MRI: magnetic resonance imaging; mtDNA: mitochondrial DNA; NCOA4: nuclear receptor coactivator 4; PCBP: poly(rC) binding protein; ROS: reactive oxygen species; RT-qPCR: real-time quantitative reverse transcription; SOFG: safranin O and fast green; WWTR1/TAZ: WW domain containing transcription regulator 1; TEAD1: TEA domain transcription factor 1; TEM: transmission electron microscopy; YAP1: Yes1 associated transcriptional regulator; ZBP1: Z-DNA binding protein 1; Z-DNA: Z-form DNA; Z-mtDNA: Z-form mitochondrial DNA.
Folic acid protects against antigen-induced vascular injury via the CD36-autophagy-lysosomal axis.
Qiu J, Jiang J, Quan Y … +8 more , Zhang C, Gao N, Wang K, Guo J, Shi W, Wang G, Jiang L, Yang Y
Autophagy · 2026 May · PMID 42153647 · Publisher ↗
Whether and how pathogen-derived antigens themselves drive vascular injury remains an unresolved question in infection biology and cardiovascular research. Using murine model and human pluripotent stem cell-derived vascu...
Whether and how pathogen-derived antigens themselves drive vascular injury remains an unresolved question in infection biology and cardiovascular research. Using murine model and human pluripotent stem cell-derived vascular organoids (VOs), we demonstrate that () infection or exposure to its soluble tachyzoite antigens (STAg) compromises vascular integrity, leads to the impairment of endothelium, and heightens inflammation. Mechanistically, STAg upregulates the scavenger receptor CD36 on endothelial cells (ECs), reprogramming them toward a scavenger endothelial cell (SEC)-like phenotype. This shift enhances CD36‑dependent antigen uptake and subsequently perturbs the macroautophagy/autophagy-lysosomal pathway (ALP), culminating in cellular homeostasis disruption. Interestingly, prophylactic folic acid (FA) ameliorates STAg-induced vascular injury. FA acts by suppressing CD36 expression, thereby limiting STAg uptake and attenuating ALP hyperactivation, together preserving vascular integrity at the molecular, structural, and metabolic levels. To our knowledge, this study provides the first evidence that pathogen-derived proteins can reprogram ECs into an SEC-like phenotype in a CD36‑dependent manner, with subsequent dysfunction of ALP. Our findings not only identify pathogen-derived proteins as novel mediators of vascular injury but also establish the CD36-ALP axis as a promising therapeutic target. Furthermore, we propose FA as a potent vascular-protective agent.: ALP: autophagy-lysosomal pathway; Chlo: chloroquine; ECs: endothelial cells; ECM: extracellular matrix; ER: endoplasmic reticulum; FA: folic acid; RAPA: rapamycin; SMCs: smooth muscle cells; STAg: soluble tachyzoite antigens; : ; TLRs: toll-like receptors; VOs: vascular organoids.
Feedback loops between DNMT1 and autophagy as well as senescence promotes organ aging and canities.
Li L, Mao X, Li LX … +6 more , Xiao H, Lou Z, Liu H, Zhou JX, Yao L, Li X
Autophagy · 2026 May · PMID 42153573 · Publisher ↗
Alternations of DNA methylation occur in aging, which is regulated by DNA methyltransferases (DNMTs). In this study, we show that even though the transcription of DNMT1, the only enzyme that maintains DNA methylation in...
Alternations of DNA methylation occur in aging, which is regulated by DNA methyltransferases (DNMTs). In this study, we show that even though the transcription of DNMT1, the only enzyme that maintains DNA methylation in the mammalian genome, is reported to be decreased in an age-dependent manner, the decrease of mRNA does not result in a decrease of its protein. Instead, DNMT1 protein is increased in aged mouse tissues, which is responsible for the methylation of genes related to macroautophagy/autophagy, senescence repression, and melanin synthesis and transport in aged organs, resulting in a decline of autophagy, an increase of senescence in those organs, and a decrease in melanin production in hair follicles (canities) in response to ionizing radiation (IR). Genetic deletion and inhibition of DNMT1 can reverse these processes. The interaction of DNMT1 with ATG7 through its CXXC domain is essential for its degradation, and treatment with senolytics also downregulates DNMT1 in aged organs, supporting two feedback loops between them.: 4-OHT, 4-hydroxytamoxifen; ChIP, chromatinimmunoprecipitation; D, dasatinib; D-gal, D-galactose; DCT/Trp-2, dopachrometautomerase; DMRs, differentially methylated regions; DNAm, DNA methylation; DNMTs,DNA methyltransferases; DSBs, double-stranded breaks; ETO, etoposide; GST, glutathione-S-transferase; HEK293T,human embryonic kidney 293T; HEM, human epidermal melanocytes; Hydr, hydralazine;IP, immunoprecipitation; IR, ionizingradiation; KIF1A, kinesin family member 1A; M, methylated; MmIMCD3,mouse inner-medullary collecting duct 3; MITF, melanocyte inducingtranscription factor; MSP, methylation specific PCR; NCBI, national center for biotechnologyinformation; N-me, N-methyladenosine; PBMCs, peripheral blood mononuclear cells;Pro, proliferating; Q, quercetin; Rapa, rapamycin; RRBS, reduced representationbisulfite sequencing; RT, reverse transcription; SA-GLB1/β-Gal, senescence-associatedgalactosidase beta 1; SASP, senescence-associated secretory phenotype; Sen, senescent; SNP, single nucleotidepolymorphism; TYR, tyrosinase; TYRP1/Trp-1, tyrosinase related protein 1; UHRF1,ubiquitin like with PHD and ring finger domains 1; UM, unmethylated; UTR, untranslatedregion; WGBS, whole-genome bisulfite sequencing.
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