Biochimica Et Biophysica Acta[JOURNAL]
Sun
200 papers
SF3B3-dependent inclusion of STOX1 exon 3 facilitates invasion and tumor progression in colorectal cancer.
Zhou L, Guo Z, Yu L … +6 more , Traore AGY, Yu Z, Huang Q, Cao Y, Zheng Q, Wang F
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42361929 · Publisher ↗
Alternative splicing dysregulation contributes to colorectal cancer (CRC) progression, yet the roles of specific splicing factors, such as SF3B3, remain poorly defined. To identify key dysregulated splicing factors, RNA...
Alternative splicing dysregulation contributes to colorectal cancer (CRC) progression, yet the roles of specific splicing factors, such as SF3B3, remain poorly defined. To identify key dysregulated splicing factors, RNA sequencing was performed comparing high-metastatic (SW620) and low-metastatic (SW480) CRC cell lines. Notably, SW480 and SW620 are isogenic cell lines derived from the primary tumor and lymph node metastasis of the same CRC patient, respectively. Their consistent genetic background minimizes confounding factors, enabling reliable detection of metastasis-associated molecular alterations. Functional assays-including MTT, wound healing, and transwell experiments-combined with molecular analyses confirmed the critical role of the SF3B3-STOX1 axis. SF3B3 was markedly upregulated in metastatic CRC cells and patient tissues. Mechanistically, SF3B3 promoted CRC cell proliferation, migration, and invasion by modulating STOX1 alternative splicing, specifically enhancing exon 3 inclusion to produce the oncogenic isoform STOX1-L while suppressing STOX1-S. Notably, STOX1-L, but not STOX1-S, robustly activated the PI3K-AKT and MAPK/ERK signaling pathways. Importantly, knockdown of STOX1-L reversed the malignant phenotypes driven by SF3B3. Collectively, these results identify SF3B3 as a pivotal regulator of CRC cell metastasis in the isogenic SW480/SW620 cell model that acts through the production of STOX1-L, establishing the SF3B3-STOX1-L axis as a promising candidate therapeutic target for advanced colorectal cancer worthy of further validation in diverse CRC models.
Targeting the KMT2D-driven Enhancer-Immune-Metabolic axis in HNSCC: Reconciling the paradox for precision therapy.
Wang K, Lu H, Deng N … +8 more , Tao Y, Yang X, Yuan M, Gao L, Jiang S, Shang W, Deng J, Wang L
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42349694 · Publisher ↗
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) carries a substantial mortality burden, driven largely by locoregional recurrence. Although immune checkpoint blockade (ICB) is now standard-of-care for recurrent...
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) carries a substantial mortality burden, driven largely by locoregional recurrence. Although immune checkpoint blockade (ICB) is now standard-of-care for recurrent/metastatic disease, primary resistance and limited durability remain major barriers. Clinical outcomes are not determined by PD-L1 status alone, but instead emerge from a multidimensional tumor ecosystem shaped by genomic alterations and epigenetic-metabolic reprogramming. KMT2D (MLL4), a frequently mutated histone methyltransferase in HNSCC, exemplifies this complexity: it is traditionally regarded as a differentiation-preserving tumor suppressor, yet accumulating data suggest context-dependent roles in sustaining oncogenic stemness and metabolic fitness. MAIN BODY: This review reconciles these seemingly discordant observations through an "Enhancer-Immune-Metabolic Framework," positioning KMT2D as an epigenetic rheostat rather than a binary determinant. We synthesize evidence that KMT2D alteration rewires enhancer landscapes, with particular emphasis on the PER2 axis, to promote a shift toward aerobic glycolysis. We further discuss how this metabolic state can potentiate immune exclusion by dampening antigen presentation programs and by supporting an immunosuppressive myeloid milieu. A central mechanistic link highlighted here is histone lactylation (e.g., H3K18la), proposed to couple glycolytic flux to chromatin remodeling and transcriptional outputs that favor immune evasion. Building on these concepts, we outline translationally actionable vulnerabilities in KMT2D-altered tumors, including: (i) synthetic lethal strategies with PARP inhibitors, (ii) metabolic blockade to disrupt glycolysis-associated immune suppression, and (iii) epigenetic "priming" approaches to re-open enhancers governing antigen presentation and T cell-inflamed states, thereby enhancing ICB responsiveness. CONCLUSIONS: KMT2D-driven enhancer remodeling provides a unifying lens to connect metabolic reprogramming with immune escape in HNSCC. Conceptualizing KMT2D as an epigenetic rheostat supports biomarker-informed combination strategies-integrating DNA damage repair targeting, metabolic interventions, and epigenetic priming-to overcome ICB resistance and improve durable disease control in KMT2D-altered HNSCC.
Retraction notice to "Assessment of cytotoxic and genotoxic potentials of a mononuclear Fe(II) Schiff base complex with photocatalytic activity in Trigonella" [Biochimica et Biophysica Acta (BBA) - General Subjects 1864 (2020) 129503].
Mahapatra K, Ghosh AK, De S … +6 more , Ghosh N, Sadhukhan P, Chatterjee S, Ghosh R, Sil PC, Roy S
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42342531 · Publisher ↗
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HSP27 in autoimmune diseases: Context-dependent regulation and clinical potential.
Li J, Li R, Wang W … +2 more , Gesang Y, Liu W
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42342167 · Publisher ↗
BACKGROUND: Heat shock protein 27 (HSP27) is a crucial member of the small heat shock protein family with a molecular weight of approximately 27 kDa, playing key roles in cellular stress response, protein homeostasis, an...
BACKGROUND: Heat shock protein 27 (HSP27) is a crucial member of the small heat shock protein family with a molecular weight of approximately 27 kDa, playing key roles in cellular stress response, protein homeostasis, and cell survival regulation. Recent studies have revealed that HSP27 plays a complex dual role in the pathogenesis of autoimmune diseases, which we define as the "HSP27 Dual Regulatory Paradox." Aim To systematically review the bidirectional immunomodulatory mechanisms of HSP27 in autoimmune diseases and to evaluate its clinical potential as a disease biomarker and therapeutic target, based on a "cell type-microenvironment-disease stage" three-dimensional regulatory model. METHODS: A comprehensive literature review was conducted using PubMed and other databases up to 2025, focusing on the structural characteristics, biological functions, and immunoregulatory roles of HSP27 in typical autoimmune diseases including Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Behçet's disease, psoriasis, myasthenia gravis, systemic sclerosis, type 1 diabetes, and inflammatory bowel disease. RESULTS: HSP27 exhibits a context-dependent dual regulatory role: in structural cells such as synovial fibroblasts, it acts as an essential component of the TAK1-p38 MAPK-MK2 signaling pathway, promoting pro-inflammatory mediators (IL-6, IL-8); in the monocyte-macrophage system, it induces IL-10 secretion and limits IL-1β release. Anti-HSP27 antibody positivity reaches 72% in rheumatoid arthritis and 57% in Behçet's disease patients. HSP27 expression correlates with disease activity across multiple autoimmune conditions and shows disease-specific patterns: neuroprotective in multiple sclerosis, anti-apoptotic in lupus nephritis, and pro-inflammatory in rheumatoid synovium. HSP27-targeted therapeutic strategies, including small-molecule inhibitors (OGX-427, RP101, J2), antisense oligonucleotides, and HSP-based immune tolerance induction, are under preclinical and clinical evaluation. CONCLUSION: HSP27 represents a multifaceted molecular target in autoimmune diseases, with its function determined by the interplay of cell type, microenvironment, and disease stage. A thorough understanding of this three-dimensional regulatory model will provide an important theoretical basis for developing novel diagnostic markers and precision-targeted therapeutic strategies. Future studies integrating single-cell sequencing, spatial omics, and large-scale clinical cohorts are needed to translate HSP27 biology into clinical applications.
MAPK/c-Jun/TNNT1 pathway regulates cytoskeletal remodeling and promotes tumor invasion and metastasis in HNSCC.
Xie J, Lin X, Chen G … +5 more , Zheng G, Lin S, Zhao Y, Lu Y, Zheng D
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42342166 · Publisher ↗
BACKGROUND: Metastasis in head and neck squamous cell carcinoma (HNSCC) significantly reduces patient survival, but its molecular mechanisms remain incompletely understood. This study aims to investigate the role and reg...
BACKGROUND: Metastasis in head and neck squamous cell carcinoma (HNSCC) significantly reduces patient survival, but its molecular mechanisms remain incompletely understood. This study aims to investigate the role and regulatory mechanism of troponin T1 (TNNT1) in HNSCC metastasis. METHODS: Low-metastatic (CAL27) and high-metastatic (LN4) HNSCC cell lines were used for RNA-seq analysis to identify differentially expressed genes. The impact of TNNT1 on cell migration, invasion, and metastasis was validated through in vitro scratch healing, Transwell assays, cytoskeleton staining, and in vivo orthotopic xenograft models in nude mice. IHC, Western blot, ChIP, and pharmacological inhibitors were employed to analyze TNNT1's upstream regulatory pathways and downstream mechanisms. RESULTS: TNNT1 expression in metastatic HNSCC correlates with poor survival and promotes metastasis through cytoskeletal remodeling. Knockdown suppresses migration and invasion, while overexpression has the opposite effect. TNNT1 induces EMT by altering F-actin and activating MMPs/FAK. The MAPK pathway and c-Jun transcription factor upregulate TNNT1, which JNK-IN-8 can inhibit, reversing cytoskeletal changes and suppressing metastasis in vitro and in vivo. CONCLUSIONS: TNNT1 facilitates metastasis in HNSCC by remodeling the cytoskeleton to promote epithelial-mesenchymal transition. Its expression is transcriptionally controlled by the MAPK/c-Jun signaling pathway. Targeting TNNT1 or its upstream pathways, such as inhibitors of JNK, could offer new therapeutic approaches to prevent HNSCC metastasis.
Immunoediting characteristics and immunotherapy strategy optimization in HBV-related hepatocellular carcinoma.
Zhu J, Zhang H, Wang Z … +1 more , Cheng S
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42342165 · Publisher ↗
Hepatocellular carcinoma (HCC) is a globally prevalent malignant tumor with high mortality, and chronic hepatitis B virus (HBV) infection is its most important risk factor. The occurrence and progression of HBV-related H...
Hepatocellular carcinoma (HCC) is a globally prevalent malignant tumor with high mortality, and chronic hepatitis B virus (HBV) infection is its most important risk factor. The occurrence and progression of HBV-related HCC (HBV-HCC) are closely associated with the dynamic immunoediting process (elimination, equilibrium, escape) modulated by chronic HBV infection, which reshapes the tumor immune microenvironment (TIME) and regulates immune cell function, thereby affecting tumor fate. Although immune checkpoint inhibitors (ICIs) and related combination therapies have achieved breakthroughs in HBV-HCC treatment, the highly immunosuppressive TIME and tumor heterogeneity lead to significant therapeutic response differences and limitations, especially in special populations. This review systematically outlines the immunoediting process of HBV-HCC, evaluates current immunotherapy limitations, and proposes optimized strategies for clinical translation.
ST3GAL1 mediates sialylation to promote adhesion of Fusobacterium nucleatum to colorectal cancer cells.
Xiao L, Gong T, Luo W … +5 more , Jiang Y, Peng X, Zhou X, Cheng L, Zheng X
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42342164 · Publisher ↗
Fusobacterium nucleatum is a commensal bacterium in the oral cavity and is closely related to several oral infectious diseases. In addition to oral colonization, F. nucleatum is enriched in colorectal cancer (CRC) and is...
Fusobacterium nucleatum is a commensal bacterium in the oral cavity and is closely related to several oral infectious diseases. In addition to oral colonization, F. nucleatum is enriched in colorectal cancer (CRC) and is closely associated with CRC progression, while the mechanism of F. nucleatum adhesion to cancer cells has not been fully explained. Sialylation is of high levels in CRC and host cell surface sialoglycans are considered as potential targets for microorganism adhesion. However, the effect of excessive sialylation in CRC on the adhesion of gut microorganisms remains unknown. Here we found that high sialylation level mediated by ST3GAL1 in CRC is closely associated with F. nucleatum adhesion. Knockdown or overexpression of ST3GAL1 significantly affected F. nucleatum adhesion level in vitro and in vivo. In addition, F. nucleatum enables its colonization and cancer-promoting effect via upregulation of H3K27 acetylation and ANGPTL4 expression. Together, our study revealed a link between host sialylation and F. nucleatum adhesion, providing a new insight into F. nucleatum intratumoral retention and persistence in CRC.
DNMT3B attenuates the development of thoracic aortic aneurysm and dissection by suppressing TFEB-mediated autophagy in vascular smooth muscle cells.
Bao Y, Zhu Y, Niu Y … +4 more , Hu Y, Lu D, Xu R, Fan X
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42342163 · Publisher ↗
While emerging evidence highlights the importance of DNA methyltransferase 3B (DNMT3B) in cardiovascular pathophysiology, its precise role in thoracic aortic aneurysm and dissection (TAAD) remains poorly understood. Here...
While emerging evidence highlights the importance of DNA methyltransferase 3B (DNMT3B) in cardiovascular pathophysiology, its precise role in thoracic aortic aneurysm and dissection (TAAD) remains poorly understood. Here, we elucidate the function and underlying mechanisms of DNMT3B in TAAD pathogenesis. We found that DNMT3B expression was markedly downregulated in vascular smooth muscle cells (VSMCs) of both human and mouse TAAD tissues compared to healthy controls. In vivo, targeted overexpression of DNMT3B in VSMCs via adeno-associated virus delivery significantly decreased TAAD incidence, reduced aortic rupture rates, and attenuated aortic dilation. Conversely, VSMC-specific DNMT3B knockdown exacerbated disease progression. In vitro experiments, utilizing adenovirus-mediated overexpression and the inhibitor Nanaomycin A revealed that DNMT3B inhibits both VSMC autophagy and phenotypic switching. Mechanistically, DNMT3B prevents the maladaptive transition of VSMCs toward a synthetic phenotype through the transcriptional repression of transcription factor EB (TFEB), thereby curbing excessive autophagy. Collectively, our findings demonstrate a protective role for DNMT3B against TAAD, highlighting its function in preserving VSMC homeostasis via the transcriptional inhibition of TFEB.
The irisin-PINK1/Parkin axis plays an essential role in mediating microglial mitophagy: A crucial mechanism for exercise-induced neuroprotection against Parkinson's disease.
Wang B, Liu X, Tian X … +4 more , Lin J, Li Q, Wu Y, Zhao R
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42342162 · Publisher ↗
The progression of Parkinson's disease (PD) is primarily driven by chronic neuroinflammation in microglia and impaired mitochondrial quality control. Here, we show that 10 weeks of treadmill running ameliorates motor def...
The progression of Parkinson's disease (PD) is primarily driven by chronic neuroinflammation in microglia and impaired mitochondrial quality control. Here, we show that 10 weeks of treadmill running ameliorates motor deficits, dopaminergic neuron loss, and α-synuclein (α-syn) pathology in MPTP-induced PD mice. Exercise enhances PINK1/Parkin-dependent mitophagy in microglia, evidenced by increased LC3/Iba1 colocalization, p62 clearance, and direct LC3/Tom20 colocalization, thereby suppressing proinflammatory activation. These effects are mediated by exercise-induced upregulation of FNDC5/irisin. In vitro, recombinant irisin rescues impaired mitophagy and alleviates neuroinflammation in α-syn-exposed microglia. Crucially, pharmacological blockade of irisin receptors with RGDyk abolishes exercise-induced neuroprotection, mitophagy restoration, and behavioral improvements. Our findings reveal: (1) Exercise alleviates PD pathology by enhancing mitochondrial autophagy to reprogram microglial function; (2) Irisin is a key myokine activating microglial mitochondrial autophagy via the PINK1/Parkin pathway; (3) The irisin-mitochondrial autophagy axis represents a novel and promising therapeutic target for PD. This work provides the first evidence that exercise-induced irisin directly regulates microglial mitochondrial homeostasis, establishing a mechanistic basis for exercise-based PD interventions.
Extracellular matrix stiffness primes the NLRP3-Inflammasome by promoting NLRP3 gene expression via FAK/mTOR/nuclear-actin/SREBP signalling in vascular smooth muscle cells.
Hadfield L, McNeill M, Sekar V … +3 more , Ebrahimighaei R, Newby A, Bond M
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42341888 · Publisher ↗
Arterial stiffening is associated with an increased risk of cardiovascular disease (CVD) morbidity and mortality. We investigated the effects of ECM-stiffness on the expression of NLRP3, a component of the NLRP3-inflamma...
Arterial stiffening is associated with an increased risk of cardiovascular disease (CVD) morbidity and mortality. We investigated the effects of ECM-stiffness on the expression of NLRP3, a component of the NLRP3-inflammasome. VSMC interacting with a stiff (50 kPa) ECM displayed elevated expression of NLRP3 protein and mRNA, compared to cells interacting with a soft (2 kPa) ECM. ECM-stiffness enhanced levels of pre-spliced NLRP3 RNA and NLRP3 promoter reporter gene activity, indicating transcriptional upregulation of the NLRP3 gene. Increased ECM stiffness increased phosphorylation of FAK and the S6 protein. ECM stiffness reduced levels of nuclear actin monomer in a FAK and mTOR-dependent manner. NLRP3 expression was dependent on FAK and mTOR and antagonised by elevated nuclear actin monomer. Analysis of the NLRP3 promoter identified an SREBP element. SREBP activity was increased in response to ECM-stiffness in a FAK, mTOR and nuclear actin monomer-dependent manner. Pharmacological or siRNA-mediated inhibition of SREBP significantly reduced NLRP3 expression. Taken together, this novel pathway helps to explain how arterial stiffening promotes a pro-inflammatory VSMC phenotype by priming the NLRP3-inflammasome.
A putative role for Mrx3 and Fmp10 in regulating yeast mitochondrial acyl-CoA thioesters.
Costa-Lima MM, Gomes F, Damaceno TR … +1 more , Barros MH
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42341887 · Publisher ↗
The hotdog-fold acyl-CoA thioesterases (ACOTs) are enzymes typically related to lipid metabolism and are widely spread across the tree of life, but many members of this group are poorly characterized. In this work, throu...
The hotdog-fold acyl-CoA thioesterases (ACOTs) are enzymes typically related to lipid metabolism and are widely spread across the tree of life, but many members of this group are poorly characterized. In this work, through in silico analyzes we identified the MICOS-associated mitochondrial proteins of unknown function Mrx3 and Fmp10 as two putative ACOTs in Saccharomyces cerevisiae with structural homology to the mammalian thioesterases Them4 and Them5, which possess a conserved motif that is catalytic toward thioester hydrolysis. Lipidomics analyses revealed that the mrx3Δ and fmp10Δ mutants have lower free fatty acid (FFA) levels with concomitant accumulation of storage lipids, besides a decreased pool of cardiolipin species. During our functional investigation, we observed that the absence of either protein partially restores respiratory capacity in the leu5Δ strain, whose mutation has been previously linked to very slow respiratory growth due to severe Coenzyme A (CoA) depletion in the mitochondrial matrix. We verified that the respiratory defect of the leu5Δ mutant is also related to a defect in the respiratory chain given the low NADH-dependent oxygen consumption rate and is specifically linked to defective Complex IV activity. The strain's growth defect was exacerbated by deletion of the glycine transporter HEM25 and was ameliorated by either δ-aminolevulinic acid (ALA, a heme precursor) or iron supplementation. These results may indicate that the leu5Δ strain has a subtle heme deficiency. We propose a model in which Mrx3 and Fmp10 control the mitochondrial acyl-CoA/CoA ratio through a thioesterase activity, which finely modulates the mitochondrial membrane lipidome, with a concomitant effect in heme biosynthesis. In the leu5Δ mutant, there is a disturbed metabolic homeostasis. Deleting these hotdog-fold proteins cause increased acyl-CoA levels and partially restores metabolic balance, potentially by repartitioning carbon flux through the tricarboxylic acid (TCA) cycle to replenish succinyl-CoA using the limited available CoA pool, which may be sufficient to restore heme biosynthesis. This mechanism highlights the critical role of CoA compartmentalization and the underlying connection of distinct metabolic pathways.
Narirutin inhibits inflammation and oxidative stress in osteoarthritis via suppressing AKT/NF-κB signaling.
Wang H, Hao L, Wu Y … +1 more , Mu W
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42341886 · Publisher ↗
Narirutin is a flavanone with anti-inflammatory and antioxidant properties. The objective of this study was to evaluate its therapeutic potential against osteoarthritis. Anterior cruciate ligament transection (ACLT) rats...
Narirutin is a flavanone with anti-inflammatory and antioxidant properties. The objective of this study was to evaluate its therapeutic potential against osteoarthritis. Anterior cruciate ligament transection (ACLT) rats were administered 10, 30, or 50 mg/kg narirutin by daily oral gavage. ATDC-5 cells were treated with 50, 100, or 200 μM narirutin in the presence of 10 ng/mL IL-1β. Extracellular matrix (ECM) degradation, inflammation, and oxidative stress in vitro and in vivo were assessed by hematoxylin and eosin and Safranin O-Fast Green staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, flow cytometry, western blotting, and immunofluorescence. In ACLT rats, narirutin ameliorated cartilage lesions, reduced the Osteoarthritis Research Society International score, and reduced serum levels of C-telopeptide of type II collagen and cartilage oligomeric matrix protein. In both ACLT rats and ATDC-5 cells, narirutin downregulated A disintegrin and metalloproteinase with thrombospondin motifs 5, matrix metalloproteinase (MMP)-3, and MMP13 and upregulated Collagen II and Aggrecan. In addition, narirutin decreased the levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, reactive oxygen species, and Malondialdehyde while increasing the levels of superoxide dismutase and glutathione. Network pharmacology analysis identified phosphoinositide 3-kinases/protein kinase B (PI3K/AKT) as a signaling pathway regulated by narirutin in osteoarthritis. Narirutin binds to AKT1 to inhibit AKT and nuclear factor-κB (NF-κB) activation. Furthermore, NF-κB overexpression and SC79 treatment reversed the anti-inflammatory and antioxidant properties of narirutin in ATDC-5 cells. Narirutin exhibited cartilage-protective effects in osteoarthritis models by inhibiting ECM degradation, inflammation, and oxidative stress through suppressing AKT/NF-κB signaling.
HSF4 promotes lipid peroxidation by transcriptionally regulating ALOX15 during lens terminal differentiation.
Zhang S, Wang Y, Jiang N … +10 more , Li X, Han L, Chen S, Xie T, Yan H, Li J, Hu Y, Mu H, Zhang J, Cui X
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jun · PMID 42341403 · Publisher ↗
Lens fibers undergo organelle degradation during lens terminal differentiation. Defects in organelle degradation of lens fibers lead to congenital cataract. As a member of heat shock factor family, HSF4 governs lens deve...
Lens fibers undergo organelle degradation during lens terminal differentiation. Defects in organelle degradation of lens fibers lead to congenital cataract. As a member of heat shock factor family, HSF4 governs lens development by regulating the expression of key factors. HSF4 transcriptionally regulates ATG9a to induce organelle degradation via the autophagic pathway during lens terminal differentiation. HSF4 is also required for the organelle membrane translocation of phospholipases PLAATs, which were suggested to promote organelle degradation independent of autophagy in lens fibers. However, the detailed mechanism how HSF4 induces organelle degradation in lens fibers still remains unknown. In this study, we found that lipid peroxidation was extensively suppressed in HSF4 mouse lens fibers. HSF4 likely transcriptionally regulated the expression of lipoxygenase ALOX15 in lens. ALOX15 is uniquely expressed in lens fibers and colocalized with organelles in differentiating lens fibers. Knockout of ALOX15 had little effect on the organelle degradation in lens fibers. Unlike the total inhibition in HSF4 lens fibers, lipid peroxidation was only partially disturbed in ALOX15 lens fibers, possibly due to the compensatory role of ALOX12. Our findings demonstrate that HSF4 promotes lipid peroxidation by transcriptionally regulating ALOX15 expression in lens fibers, thus may contribute to the organelle degradation during lens OFZ formation. These findings expand our understanding of the molecular mechanisms underlying lens terminal differentiation.
Structure of the short-form ATP-phosphoribosyltransferase from Acinetobacter baumannii reveals the presence of a novel Mg sequestering and storage site.
Ahmad N, Sharma P, Sharma S … +1 more , Singh TP
Biochim Biophys Acta Proteins Proteom · 2026 Jun · PMID 42336071 · Publisher ↗
Adenosine triphosphate phosphoribosyltransferase (ATP-PRT), a member of the phosphoribosyltransferase (PRT) superfamily of enzymes, catalyses the first step in the histidine biosynthesis pathway, which involves the nucle...
Adenosine triphosphate phosphoribosyltransferase (ATP-PRT), a member of the phosphoribosyltransferase (PRT) superfamily of enzymes, catalyses the first step in the histidine biosynthesis pathway, which involves the nucleophilic substitution of ATP onto phosphoribosyl pyrophosphate (PRPP) to generate phosphoribosyl-ATP (PR-ATP) and pyrophosphate (PP). The three-dimensional structure of short-form ATP-PRT from Acinetobacter baumannii (AbHisG) was determined using the X-ray crystallographic method. The structure determination revealed two crystallographically independent molecules in the asymmetric unit that formed an antiparallel homodimer. In all the structures of HisG proteins reported so far, the N-terminal segment is either absent from the amino acid sequence or not observed in the structure. This is the first structure where the N-terminal segment has been clearly observed. However, the most remarkable observation pertains to observing a Mg ion in the structure with the help of the N-terminal segment, which is loosely held with six coordination linkages, out of which one contact is made to the carbonyl oxygen atom of Asn16 at an average distance of 2.06 Å, and the other five contacts were with water oxygen atoms at distances varying from 2.40 to 2.59 Å. All the coordinating water oxygen atoms were held in place by multiple hydrogen bonds from surrounding protein atoms. The relatively loose coordination environment of the Mg ion indicates temporary sequestration of Mg, which may be released during catalytic need.
Gaussia luciferase: A highly unusual enzyme.
Winther JR, Dijkema FM, Vinther SK … +4 more , Espersen R, Hansen MM, Janin YL, Willemoës M
Biochim Biophys Acta Proteins Proteom · 2026 Jun · PMID 42336070 · Publisher ↗
The luciferase from the mesopelagic planktonic crustacean Gaussia princeps has garnered attention as reporter protein due to its small size and its ability to produce a very bright luminescence. Over the past two decades...
The luciferase from the mesopelagic planktonic crustacean Gaussia princeps has garnered attention as reporter protein due to its small size and its ability to produce a very bright luminescence. Over the past two decades much research has focused on the development of improved mutant variants as well as variants designed by combining sequence information from luciferases from several related copepod species. Gaussia luciferase is however of basic scientific interest because it is unusual in two main respects. First, structural analysis of Gaussia luciferase has demonstrated that this enzyme is extensively disordered with little hydrophobic core. This has complicated the identification of a substrate binding site and elucidation of the enzymatic mechanism remains obscure. Second, this luciferase is subject to rapid irreversible inactivation upon oxidation of its substrate, coelenterazine. These findings open fundamental enzymology questions and have significant implications for the use of Gaussia luciferase in life sciences; areas such as bioluminescence-based reporting assays and in high-throughput screening. Thus, past research is examined considering these recent findings, and with special emphasis on their implications for consistent assays and evaluation of mutant variants.
Biosynthesis of C-phycocyanin trimers.
Zhao X, Zhu JX, Li GC … +1 more , Zhao KH
Biochim Biophys Acta Bioenerg · 2026 Jun · PMID 42336025 · Publisher ↗
Phycobiliproteins, particularly C-phycocyanin (CPC), serve as major light-harvesting complexes in cyanobacteria, exhibiting high efficiency in light-harvesting and energy transfer. Currently, the easy and large-scale acq...
Phycobiliproteins, particularly C-phycocyanin (CPC), serve as major light-harvesting complexes in cyanobacteria, exhibiting high efficiency in light-harvesting and energy transfer. Currently, the easy and large-scale acquisition of functional CPC remains a major challenge, primarily due to the requirement for precise, sequential covalent attachment of multiple phycocyanobilin (PCB) chromophores. In this study, by using a dual-promoter (T7 and araBAD) system to control the sequential binding of two PCB chromophores to β82 and β153, we successfully achieved the biosynthesis of β-CPC (λ = 605 nm, λ = 644 nm) in E. coli, which can transfer energy from the β153-PCB to the β82-PCB. The assembly of α-CPC with PCB-β82, PCB-β153, and PCB-β under identical conditions indicates that only PCB-β, which covalently binds the two PCB chromophores, can assemble with α-CPC to form a complete CPC trimer (λ = 617 nm, λ = 646 nm). The structure of the assembled trimer reveals that it adopts a typical phycobiliprotein fold, with multiple chromophores precisely arranged, exhibiting features highly similar to those of native CPC. Furthermore, we established a biosynthetic pathway for CPC trimers in E. coli. This system provides a powerful tool for engineering phycobiliproteins with various light-harvesting and energy transfer properties, facilitating future studies on artificial photosynthesis, light-harvesting antenna design, and the fundamental mechanisms of excitation energy transfer.
Cryo-EM structure of photosystem II D1-V185T mutant from Thermosynechococcus vestitus.
Jiang H, Nakajima Y, Akita F … +4 more , Li H, Kato K, Sugiura M, Shen JR
Biochim Biophys Acta Bioenerg · 2026 Jun · PMID 42331212 · Publisher ↗
Photosystem II (PSII) catalyzes water oxidation into electrons, protons and dioxygen at its catalytic center, a MnCaO cluster, utilizing light energy. An amino acid residue D1-V185 in the D1 protein is located close to t...
Photosystem II (PSII) catalyzes water oxidation into electrons, protons and dioxygen at its catalytic center, a MnCaO cluster, utilizing light energy. An amino acid residue D1-V185 in the D1 protein is located close to the MnCaO cluster, and plays a critical role in its catalytic function. In this research we purified PSII dimers from a D1-V185T mutant of Thermosynechococcus vestitus and analyzed its structure using low-damage cryo-electron microscopy (cryo-EM) at a resolution of 1.88 Å. The results revealed the presence of multi-conformations at the mutation site. Unlike the wild-type valine, which does not allow water molecules to be able to form hydrogen-bonds with it, both conformations of the mutant formed hydrogen bonds with nearby water molecules, which leads to rearrangement of the hydrogen bond networks in the O1 and Cl-1 channels. In conformation-A, the mutated Thr residue forms a hydrogen bond with a water molecule W6, which creates a new channel that bypasses the original O1 channel. Due to the hydrophilic OH group of Thr, the side-chain of D1-Glu189 was attracted and shifted toward the mutant Thr residue. In conformation-B, it forms a hydrogen bond with a water molecule W9 in the Cl-1 channel, bringing W9 closer and thereby disrupting the hydrogen bond network of the Cl-1 channel. In addition, multi-conformations of D2-K317, which is a ligand of Cl-1, were found in the mutant. These changes alter the environment surrounding the Cl-1 ion and MnCaO, thereby affecting the PSII water-oxidation activity.
Fibroblasts carrying intermediate C9orf72 hexanucleotide repeat expansions from iNPH patients show changes in energy metabolism but no cell pathologies.
Hoffmann D, Korhonen V, Rostalski H … +12 more , Huber N, Heikkinen S, Hietanen T, Wittrahm R, Leskelä S, Hartikainen P, Rauramaa T, Solje E, Portaankorva AM, Hiltunen M, Leinonen V, Haapasalo A
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42331066 · Publisher ↗
Long C9orf72 hexanucleotide repeat expansions (C9-HRE) are the most common genetic cause of frontotemporal dementia (FTD), a group of neurodegenerative syndromes leading to cognitive dysfunction and frontal and temporal...
Long C9orf72 hexanucleotide repeat expansions (C9-HRE) are the most common genetic cause of frontotemporal dementia (FTD), a group of neurodegenerative syndromes leading to cognitive dysfunction and frontal and temporal atrophy. FTD is a potential comorbidity of idiopathic normal pressure hydrocephalus (iNPH) and carrying the C9-HRE can modify the age-of-onset in iNPH patients. While intermediate-length C9-HRE (<30 repeats) are often considered non-pathogenic, the exact pathological cutoff is unclear. In this study, we assessed whether skin fibroblasts from iNPH patients carrying intermediate C9-HRE display C9-HRE-associated pathological hallmarks and changes in cellular function. C9-HRE-associated RNA foci, present in the long (>60 repeats) C9-HRE carrier fibroblasts, were not detected in those of the intermediate carriers. The number of p62-positive puncta was significantly increased in long but not intermediate C9-HRE carrier fibroblasts, in line with p62-positive intracellular inclusions observed in a brain biopsy from the patient. Induction of autophagy did not suggest any defects in the intermediate carrier fibroblasts. Fibroblasts from the intermediate C9-HRE carriers showed upregulated glycolytic activity, possibly to counteract the slightly reduced mitochondrial respiration. This could not be observed in the long C9-HRE carrier fibroblasts. In conclusion, these data suggest that while the long C9-HRE leads to more severe cellular pathologies than intermediate C9-HRE, the latter might predispose cells to deficits in specific cellular functions, such as energy metabolism.
Beyond Raf-1 inhibition: RKIP's multifaceted roles in cellular homeostasis.
Albeloushi S, Mohammad A, Hasan A … +1 more , Al-Mulla F
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42323054 · Publisher ↗
Raf Kinase Inhibitory Protein (RKIP), also known as PEBP1, is a multifunctional modulator of intracellular signaling with pivotal roles in cellular homeostasis, cancer suppression, cardiac physiology, and neurobiology. I...
Raf Kinase Inhibitory Protein (RKIP), also known as PEBP1, is a multifunctional modulator of intracellular signaling with pivotal roles in cellular homeostasis, cancer suppression, cardiac physiology, and neurobiology. Initially characterized by its inhibition of the Raf-1/MEK/ERK cascade, RKIP has since emerged as a dynamic regulator of numerous pathways, including NF-κB, GRK2, GSK3β, and Aurora B kinase. RKIP activity is modulated through phosphorylation-dependent conformational shifts that dictate its binding partners and regulatory outcomes. In oncology, RKIP acts as a metastasis suppressor by promoting let-7 microRNA expression and inhibiting pro-metastatic genes such as HMGA2, BACH1, MMPs, and CXCR4. In the nervous system, RKIP influences synaptic signaling, pain perception, and neuroprotection, while in cardiomyocytes, it enhances β-adrenergic signaling and protects mitochondria under stress. Dysregulation of RKIP is implicated in cancer progression, heart failure, and neurodegenerative diseases. Ongoing research into pharmacological modulation of RKIP holds promise for novel therapeutic interventions across diverse pathologies.
SMN haploinsufficiency exacerbates high glucose dialysate-induced peritoneal inflammation and fibrosis via mTOR/NFκB signaling pathway.
Zhu D, Huang X, Bian S … +2 more , Li J, Qian X
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42320860 · Publisher ↗
Peritoneal dialysis (PD) is a renal replacement therapy for patients with end-stage renal disease (ESRD). However, long-term PD treatment frequently triggers peritoneal inflammation and mesothelial-to-mesenchymal (MMT),...
Peritoneal dialysis (PD) is a renal replacement therapy for patients with end-stage renal disease (ESRD). However, long-term PD treatment frequently triggers peritoneal inflammation and mesothelial-to-mesenchymal (MMT), ultimately leading to irreversible peritoneal fibrosis. In this study, a high glucose-induced peritoneal fibrosis mouse model was successfully established by intraperitoneal injection of a high-glucose (HG) peritoneal dialysate. In vitro experiments of HG-induced peritoneal fibrosis were further performed using HMrSV5 human peritoneal mesothelial cells. Exposure of Survival of motor neuron (SMN)+/- mice to PD dialysate markedly exacerbated MMT progression, increased peritoneal membrane thickness, altered peritoneal permeability, and upregulated the expression levels of proinflammatory cytokines. Administration of the mammalian target of rapamycin (mTOR) inhibitor rapamycin alleviated PD fluid-induced MMT and peritoneal fibrosis in SMN+/- mice. In vitro, SMN overexpression suppressed MMT, inflammatory response, and mTOR phosphorylation in mesothelial cells under high glucose conditions. Conversely, SMN knockdown promoted MMT, accompanied by enhanced phosphorylation of mTOR and the NFκB subunit p65. Moreover, mTOR activation reversed the inhibitory effect of SMN overexpression on NF-κB phosphorylation under high glucose conditions. Taken together, our results demonstrate that SMN haploinsufficiency aggravates high glucose-induced peritoneal inflammatory, MMT and fibrosis via the mTOR/NF-κB signaling axis. Furthermore SMN overexpression mitigates peritoneal inflammatory injury and fibrotic progression by restraining mTOR/NF-κB activation in peritoneal mesothelial cells.
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