High glucose is known to impair cognitive function in individuals with type 2 diabetes, though the precise mechanisms remain unclear. In this study, guided by lactylome analysis, we demonstrate that high glucose induces...High glucose is known to impair cognitive function in individuals with type 2 diabetes, though the precise mechanisms remain unclear. In this study, guided by lactylome analysis, we demonstrate that high glucose induces HSD17B10 K105 lactylation in hippocampal neurons by upregulating lactyltransferase Aars1, which reduces HSD17B10 enzyme activity, subsequently resulting in impaired breakdown and excessive accumulation of lipid droplets, and ultimately leading to neuronal apoptosis and cognitive decline. Notably, a short peptide that competitively inhibits HSD17B10 K105 lactylation remarkably mitigates cognitive impairment in diabetic mice. Furthermore, results from a large-scale prospective cohort study reveal that elevated plasma HSD17B10 K105 lactylation serves as an independent predictor of cognitive dysfunction in patients with type 2 diabetes. These findings uncover a critical pathway linking high glucose-induced lactylation to lipid accumulation and neuronal cell death, highlighting promising molecular targets for the prevention and treatment of diabetes-associated cognitive impairment.
A growing body of evidence supports the contribution of the long-lasting adaptive immune system in Parkinson's disease (PD). We showed that the PD-associated protein PINK1 negatively regulates the presentation of mitocho...A growing body of evidence supports the contribution of the long-lasting adaptive immune system in Parkinson's disease (PD). We showed that the PD-associated protein PINK1 negatively regulates the presentation of mitochondrial antigens (MitAP) on MHC-I molecules. In vivo evidence indicated that MitAP activation in mice, in the absence of PINK1, led to cytotoxic CD8 T cell stimulation and severe motor impairments, reversible by L-DOPA. We show here that following TLR4 activation, MitAP is engaged through a pathway involving cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING), which acts as a rheostat to dampen the unfolded protein response (UPR). Without STING, the stress response is amplified, leading to a translational attenuation that inhibits the expression of XBP1s, a transcription factor required for MitAP. STING activity also regulates the repertoire of peptides displayed at the cell surface during inflammation, highlighting a potential role in immunosurveillance. These findings establish STING and the UPR as key immune regulators targetable for therapeutic intervention during autoimmune diseases and PD.
Multiple sclerosis (MS) is a neuroinflammatory disease of the CNS characterized by demyelinating lesions. Lesion expansion contributes to disability progression, whereas remyelination may restore neurological function. H...Multiple sclerosis (MS) is a neuroinflammatory disease of the CNS characterized by demyelinating lesions. Lesion expansion contributes to disability progression, whereas remyelination may restore neurological function. How these divergent outcomes relate to microglial states remains incompletely understood. Using single-cell-resolution spatial transcriptomics, we compare lesions containing foamy to those containing ramified microglia in postmortem human brain tissue. We find distinct cellular and molecular signatures spatially associated with microglial morphology. Lesions with ramified microglia display gene expression profiles associated with myelin stability and axonal support, consistent with an environment permissive for repair. In contrast, lesions with foamy microglia exhibit immune activation, immunoglobulin production, complement activity, iron dysregulation, immune-oligodendrocytes, and demyelination. These findings show that molecular programs linked to lesion pathology are spatially segregated in association with microglial state, indicating distinct immune-glial niches associated with lesion expansion and repair.
Social homeostasis-the maintenance of stable social contact-is disrupted by acute social stressors such as isolation. While the lateral habenula (LHb) is known for encoding negative emotional salience, it also modulates...Social homeostasis-the maintenance of stable social contact-is disrupted by acute social stressors such as isolation. While the lateral habenula (LHb) is known for encoding negative emotional salience, it also modulates social behavior. However, how the LHb contributes to restoring social balance after acute stress remains unclear. Here, we demonstrate that acute social isolation upregulates serotonin receptor 4 (5-HTR) expression in the LHb. Electrophysiological analysis shows impaired long-term depression and facilitated long-term potentiation in isolated mice, which is restored by pharmacological activation of 5-HTR. Behaviorally, group-housed mice show the typical social preference for novelty. On the other hand, isolated mice interact more with familiar mice than novel mice, which is restored by LHb-targeted 5-HTR activation. These findings suggest that social isolation shifts social preference through 5-HTR-mediated metaplasticity in the LHb. This study provides mechanistic insight into how acute social stress alters social behavior, with implications for social dysfunction in neuropsychiatric disorders.
Nguyen-Vigouroux C, Carraz-Billat E, Cetenovic T
… +15 more, Galleri-Paris C, Protin J, Canet-Jourdan C, Dornier E, Polrot M, Cartry J, Boilève A, Bedja S, Mérand R, Bani MA, Hollebecque A, Ducreux M, Mathieu JRR, Jaulin F, Peglion F
The metastatic dissemination of individual cells or cell collectives is a decisive step in the progression of cancers. Migrating single cells dynamically switch between mesenchymal traction-based and amoeboid propulsion-...The metastatic dissemination of individual cells or cell collectives is a decisive step in the progression of cancers. Migrating single cells dynamically switch between mesenchymal traction-based and amoeboid propulsion-based modes of migration in a mechanism named plasticity. Collective cell migration has mainly been described as a traction-dependent mode of locomotion. While a propulsive collective cell migration has recently been reported, we question whether cell clusters are also endowed with plasticity. Here, we report that patient-derived digestive cancer organoids exhibit a preferred mode of migration but transition to the alternate strategy to adapt to external stimuli or to the manipulation of intrinsic determinants. We show that the tumor cell cluster plasticity observed in vitro ensures efficient metastatic seeding in a murine model of peritoneal carcinomatosis. These findings reveal an adaptive mechanism at play during tumor invasion that must further be decrypted to enable the design of therapeutic strategies halting metastatic progression.
Tsuruta A, Hirao N, Shibata M
… +14 more, Yoshida Y, Izumi Y, Shindo N, Shiiba Y, Higashi K, Inoki T, Kai Y, Hiraoka Y, Yamauchi T, Ojida A, Bamba T, Matsunaga N, Koyanagi S, Ohdo S
The circadian clock regulates diverse immune functions, yet the role of clock components in macrophage inflammation remains controversial, with both pro- and anti-inflammatory effects reported. Here, we identify a previo...The circadian clock regulates diverse immune functions, yet the role of clock components in macrophage inflammation remains controversial, with both pro- and anti-inflammatory effects reported. Here, we identify a previously unrecognized mechanism by which the core circadian clock component BMAL1 enhances the inflammatory response of macrophages through the nuclear translocation of the peroxisomal β-oxidation enzyme multi-functional protein 2 (MFP2). BMAL1 drives MFP2 accumulation in the nucleus, where MFP2 contributes to acetyl-CoA production and acetylation of the NF-κB subunit p65, thereby facilitating M1 polarization and inflammatory chemokine expression. Nuclear MFP2 levels oscillate in a diurnal manner in the liver, but this rhythmicity is abolished in Bmal1-deficient mice. Macrophage-specific deletion of BMAL1 alleviates diethylnitrosamine-induced hepatic inflammation and tumorigenesis, concomitant with reduced inflammatory gene expression. These findings uncover a BMAL1-dependent nuclear metabolic pathway that links circadian regulation of macrophage inflammation and suggest that targeting nuclear MFP2 may offer a therapeutic approach for inflammatory diseases and tumorigenesis.
Physiological bilirubin exerts protective effects against ischemic stroke, but its role in post-stroke white matter injury (WMI) remains unclear. Here, through integrated epidemiological, genetic, and mechanistic studies...Physiological bilirubin exerts protective effects against ischemic stroke, but its role in post-stroke white matter injury (WMI) remains unclear. Here, through integrated epidemiological, genetic, and mechanistic studies, we demonstrate that mild elevation of serum bilirubin mitigates ischemic WMI by modulating B cell immunometabolism. Prospective cohort and Mendelian randomization analyses revealed an inverse association between bilirubin levels and WMI severity. In experimental models, bilirubin suppressed B cell activation and neuroinflammation by targeting transferrin receptor (TFRC), thereby reducing iron overload, restoring glucose metabolism, and improving mitochondrial homeostasis. Single-cell profiling further linked bilirubin-mediated B cell modulation to attenuated microglial activation via Fcγ receptor signaling. The existence of a bilirubin-B cell immunometabolism axis bridges preclinical findings with clinical relevance. Our findings establish bilirubin as a key immunometabolic checkpoint in B cells and propose TFRC blocking as a therapeutic strategy for ischemic WMI.
Maturation of antibody responses entails B cell Aicda/AID and Prdm1/BLIMP-1 expression for SHM/CSR, plasma cell differentiation, and production of class-switched high-affinity antibodies. We determined that TET1, TET2, a...Maturation of antibody responses entails B cell Aicda/AID and Prdm1/BLIMP-1 expression for SHM/CSR, plasma cell differentiation, and production of class-switched high-affinity antibodies. We determined that TET1, TET2, and TET3 are not expressed in resting naïve B lymphocytes, and only TET2 is induced in differentiating B cells for AID and BLIMP-1 expression. B cell TET2 recruits OGT, a metabolic sensor and sole protein O-GlcNAcylator, for O-GlcNAcylation of itself and chromatin H2B-S112. TET2 O-GlcNAcylation supports TET2-mediated active DNA demethylation (5mC oxidation to 5hmC) of Aicda and Prdm1 loci. This, together with these loci H2B-S112 O-GlcNAcylation, promotes Aicda/AID and Prdm1/BLIMP-1 expression for maturation of T-dependent and T-independent antibody responses. TET2 recruits OGT through its C-terminal-end, as evidenced by Tet2 C-terminal-end deletion mutant and AlphaFold 3.0-modeled TET2-DNA-OGT complex. Finally, B cell TET2 takes metabolic cues for Aicda/AID and Prdm1/BLIMP-1 expression, as shown by fumarate inhibition and vitamin C activation of TET2 in humanized THX mice and TcrβTcrδ mice.
Harris Snell P, Naeli P, Garzia A
… +19 more, Chen Y, Waldron JA, Chatterjee S, McGirr T, Kilmartin A, Mohammad Almomani ES, Kelsall IR, Ladak RJ, Choi JH, Luo J, Leino SA, Jess N, Shariati SA, Soto X, Gkogkas CG, Sonenberg N, Tuschl T, Maguire S, Jafarnejad SM
mRNA translation and stability are tightly regulated and functionally linked through cis-acting sequence elements and trans-acting factors, including RNA-binding proteins (RBPs). Here, we report that two chordate-specifi...mRNA translation and stability are tightly regulated and functionally linked through cis-acting sequence elements and trans-acting factors, including RNA-binding proteins (RBPs). Here, we report that two chordate-specific paralogous RBPs, ZC3H7A and ZC3H7B, preferentially bind the coding region (CDS) and 3' untranslated region (3' UTR) of A/U-rich mRNAs, particularly those with enrichment of A/U at their wobble sites (A/U3 codons). Upon binding to target mRNAs, ZC3H7A/B promote mRNA degradation through recruitment of the CCR4-NOT deadenylase complex. Furthermore, these proteins engage ribosomes lacking elongation factors and repress translation initiation via the GIGYF2/4EHP translation repressor complex. Depletion of ZC3H7A/B or 4EHP impairs the translational repression of A/U3-rich mRNAs. Together, these findings reveal a mechanism in higher eukaryotes that links A/U-rich sequence content within the CDS and 3' UTR to the coordinated post-transcriptional regulation of mRNA stability and translation.
Boulton A, Kabra A, Achille N
… +14 more, Adelman ER, Anastasakis DG, Beckedorff F, Reddy Cingaram PK, Roller DG, Zhang Y, Leach B, Gioeli D, Shiekhattar R, Yokoyama A, Hafner M, Figueroa M, Zeleznik-Le N, Bushweller JH
MLLT3 (AF9) is a critical regulator of hematopoiesis. The YEATS domain of MLLT3 binds to acylated histones (H3K9ac/cr). We showed that the YEATS domain also binds to RNA. PAR-CLIP data demonstrated binding to the snRNA 7...MLLT3 (AF9) is a critical regulator of hematopoiesis. The YEATS domain of MLLT3 binds to acylated histones (H3K9ac/cr). We showed that the YEATS domain also binds to RNA. PAR-CLIP data demonstrated binding to the snRNA 7SK. Biochemical studies show high-affinity binding to stem loop 4 (SL4) of 7SK. NMR chemical shift perturbation mapping of the binding site for 7SK SL4 on the YEATS domain was used to generate a model of the complex. Based on the model, mutations were identified that disrupt 7SK binding without affecting H3K9ac binding. Introduction of these mutations into full-length MLLT3 skewed hematopoiesis toward the lymphoid lineage, abrogated the transforming properties of NES-AF9, and reduced the self-association of MLLT3. PRO-Seq and RNA-Seq identified genes driving the observed phenotype and showed a block in transcriptional initiation with the loss of RNA binding. Our results demonstrate a critical role for RNA binding in the function of MLLT3.
Tumor-infiltrating lymphocyte (TIL) therapies harness tumor-specific T cells endogenous to a patient's repertoire but their efficacy is limited by challenges such as low frequencies of tumor-specific clonotypes and dysfu...Tumor-infiltrating lymphocyte (TIL) therapies harness tumor-specific T cells endogenous to a patient's repertoire but their efficacy is limited by challenges such as low frequencies of tumor-specific clonotypes and dysfunctional T cell phenotypes. These challenges necessitate technologies to engineer and reprogram endogenous tumor-specific TILs ex vivo. Here, we present a strategy using engineered virus-like particles (eVLPs) pseudotyped with peptide-major histocompatibility complexes (pMHCs) as a programmable, single-effector platform for selective and coordinated priming, expansion, and genome editing of rare antigen-specific CD8 T cells among their endogenous polyclonal repertoires. We demonstrate that pMHC-pseudotyped eVLPs (pMHC-eVLPs) deliver T cell function-enhancing base editors to arm polyclonal lymphocytes with enhanced anti-tumor cytotoxicity by selectively expanding and engineering the tumor-specific T cell compartment. Our work establishes pMHC-eVLPs as a platform for enhancing TIL therapy with precision gene edits without the risks of bystander T cell engineering associated with polyclonal TIL engineering approaches.
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of...The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays an essential role in innate immunity. While recent studies have revealed its critical role in non-canonical autophagy independent of its immune function, its role in selective autophagy remains elusive. Here, we identify the cGAS-STING pathway as an upstream positive regulator of mitophagy. We demonstrate that activation of TANK-binding kinase 1 (TBK1) during mitophagy is strictly dependent on the cGAS-STING pathway. Mechanistically, TBK1 activation involves the mitochondrial recruitment of STING, which requires valosin-containing protein (VCP)/p97-mediated degradation of outer mitochondrial membrane proteins. Activated TBK1 then phosphorylates optineurin (OPTN), resulting in the efficient clearance of damaged mitochondria via the autophagosome-lysosome pathway. Disruption of the STING-OPTN axis impairs mitophagy, which switches cellular response from mitophagy to apoptosis. Our work thereby defines a non-canonical, pro-survival function of the cGAS-STING pathway in mitochondrial quality control.
Cholera toxin (CT) promotes Vibrio cholerae colonization by altering gut metabolism to favor pathogen growth. Here, we show that CT-induced disease leads to the upregulation of mammalian lactate dehydrogenase A (LDHA), a...Cholera toxin (CT) promotes Vibrio cholerae colonization by altering gut metabolism to favor pathogen growth. Here, we show that CT-induced disease leads to the upregulation of mammalian lactate dehydrogenase A (LDHA), an enzyme that catalyzes the conversion of pyruvate to L-lactate, in small intestinal epithelial cells. In a suckling mouse model, the bacterial L-lactate dehydrogenase (LldD) confers a fitness advantage to V. cholerae but not to the ΔctxAB mutant incapable of producing CT. Finally, mice lacking epithelial-cell-specific LDHA have reduced luminal L-lactate concentrations, and the fitness advantage conferred by LldD is significantly reduced in these mice, demonstrating that epithelial-derived L-lactate is a major contributor to CT-dependent pathogen expansion. These findings identify epithelial-derived L-lactate as a host-derived metabolite generated in the small intestine during cholera disease that directly fuels V. cholerae growth during infection, uncovering a mechanism by which CT confers a fitness advantage to the pathogen during disease.
Stress granules are conserved biomolecular condensates that form under stress and rapidly disassemble during recovery. Stress granules have been linked to pathological protein aggregation and their impaired disassembly r...Stress granules are conserved biomolecular condensates that form under stress and rapidly disassemble during recovery. Stress granules have been linked to pathological protein aggregation and their impaired disassembly reduces cell viability, yet the mechanisms governing their clearance and protein aggregation remain unclear. We find that human HSP70 and a subset of J-domain proteins (JDPs) localize to stress granules and that chemical or genetic inhibition of these chaperones markedly slows granule disassembly. Conversely, overexpressing these JDPs, particularly DNAJB1, accelerates disassembly without altering assembly. In vitro, HSP70 and DNAJB1 partition into G3BP1 condensates and reduce their size in an ATP-dependent manner. In cells expressing amyotrophic lateral sclerosis (ALS)-linked mutant FUS, DNAJB1 depletion further impairs stress granule clearance and promotes pre-amyloid accumulation, while depleting a non-stress granule JDP has no effect. Our findings demonstrate that specific JDP chaperones enhance stress granule disassembly and help limit aberrant protein aggregation.
The mechanisms by which exercise modulates liver metabolism are poorly understood. Leveraging data from molecular transducers of physical activity consortium (MoTrPAC), we analyzed liver adaptations across 1, 2, 4, and 8...The mechanisms by which exercise modulates liver metabolism are poorly understood. Leveraging data from molecular transducers of physical activity consortium (MoTrPAC), we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omics approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) protein complexes, while male livers showed an increased acetylation of OXPHOS, tricarboxylic acid cycle, and fatty acid oxidation enzymes. Mechanistic examination revealed that these sex-specific acetylation events are partially mediated by carnitine acetyltransferase. Exercise enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Eight weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.
Cell Reports spoke with Arun K. Shukla about his scientific career, work in his lab, his mentorship experience, and the interconnectedness of science.Cell Reports spoke with Arun K. Shukla about his scientific career, work in his lab, his mentorship experience, and the interconnectedness of science.