Journal of Biological Chemistry最新文献

Small proteins CrgA and Rv0207c modulate the essential mycolic acid transporter MmpL3. 小蛋白CrgA和Rv0207c调节必需的霉菌酸转运蛋白MmpL3。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-16 DOI: 10.1016/j.jbc.2026.113658

Komal Choukate, Svitlana Babii, Wei Li, Mary Jackson, Helen I Zgurskaya

{"title":"Small proteins CrgA and Rv0207c modulate the essential mycolic acid transporter MmpL3.","authors":"Komal Choukate, Svitlana Babii, Wei Li, Mary Jackson, Helen I Zgurskaya","doi":"10.1016/j.jbc.2026.113658","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113658","url":null,"abstract":"MmpL protein complexes are major contributors to lipid/metabolite and drug transport in Mycobacterium tuberculosis and related mycobacteria and are important targets in current drug discovery efforts. At the core of these complexes are proton-motive force driven transporters belonging to the Resistance-Nodulation-cell Division superfamily of proteins that enable export of various substrates across complex bacterial cell envelopes. This study focuses on MmpL3, which transports trehalose monomycolate in M. tuberculosis and related bacterial species and plays an essential role in the assembly of the mycobacterial outer membrane. Association of MmpL3 with proteins involved in biosynthesis of mycolic acids, cell wall glycans and cell division pathways placed this transporter at the center of a complex crosstalk between various cell envelope biosynthetic processes. Here, we characterized functional interaction of MmpL3 with CrgA, a key transmembrane cell division regulatory protein, and Rv0207c, a cytoplasmic conserved mycobacterial protein. We analyzed how inactivation of CrgA and Rv0207c in vivo and their interactions with MmpL3 in vitro affect the MmpL3-dependent lipid transport activities. We found that the two proteins modulate the activities of MmpL3 and its interactions with substrates and inhibitors in a similar manner by preventing ligands access to their binding sites in the transporter. Our results provide biochemical evidence that CrgA and Rv0207c function in the same pathway and coordinate the transport activity of MmpL3 with polar cell growth and division.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113658"},"PeriodicalIF":4.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hyperpolarization-activated cyclic nucleotide-gated channels preserve excitability in ON-bipolar cells after degeneration. 超极化激活的环核苷酸门控通道在双极细胞变性后保持兴奋性。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-16 DOI: 10.1016/j.jbc.2026.113657

Jung Woong Chu, Bokeum Kang, Kyungmin Kim, Hyeonhee Roh, Uhtaek Oh, Hyungsup Kim, Yong Soo Park, Seok-Kyu Kwon, Maesoon Im, Min Soo Kim, Huan-Jun Lu, Gyu-Sang Hong

{"title":"Hyperpolarization-activated cyclic nucleotide-gated channels preserve excitability in ON-bipolar cells after degeneration.","authors":"Jung Woong Chu, Bokeum Kang, Kyungmin Kim, Hyeonhee Roh, Uhtaek Oh, Hyungsup Kim, Yong Soo Park, Seok-Kyu Kwon, Maesoon Im, Min Soo Kim, Huan-Jun Lu, Gyu-Sang Hong","doi":"10.1016/j.jbc.2026.113657","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113657","url":null,"abstract":"Retinal degeneration leads to extensive remodeling of inner retinal circuits following photoreceptor loss, but the intrinsic membrane properties of surviving bipolar cells remain incompletely understood. Here, we investigated the expression and functional contribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in ON-bipolar cells using the rd10 mouse model of retinitis pigmentosa. High-resolution fluorescence in situ hybridization showed no significant differences in Hcn1, Hcn2, and Hcn4 transcript levels between wild-type (WT) and rd10 bipolar cells. Whole-cell patch-clamp recordings detected hyperpolarization-activated inward currents consistent with Ih in both WT and rd10 ON-bipolar cells with no significant differences. In current-clamp recordings, the recovery of membrane potential following hyperpolarizing current pulses was significantly slowed by HCN channel blockers (ivabradine and ZD7288) in both genotypes. These findings indicate that HCN-sensitive conductances contribute to membrane potential recovery in ON-bipolar cells and remain detectable after photoreceptor degeneration.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113657"},"PeriodicalIF":4.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integrative proximity labeling and multiomic profiling uncover domain-specific interactomes and molecular vulnerabilities of oncogenic PI3K. 整合接近标记和多组学分析揭示了域特异性相互作用组和致癌PI3K的分子脆弱性。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-16 DOI: 10.1016/j.jbc.2026.113655

Donghee Lee, Jin Koh, Sun Hee Choi, Jong Hyuk Kim

{"title":"Integrative proximity labeling and multiomic profiling uncover domain-specific interactomes and molecular vulnerabilities of oncogenic PI3K.","authors":"Donghee Lee, Jin Koh, Sun Hee Choi, Jong Hyuk Kim","doi":"10.1016/j.jbc.2026.113655","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113655","url":null,"abstract":"Activating mutations in PIK3CA (encoding the p110α kinase) are among the most frequent oncogenic drivers in human tumors. The two major hotspot mutations, E545K (helical domain) and H1047R (kinase domain), both hyperactivate PI3K-AKT signaling, yet they exhibit distinct functional behaviors and differential drug sensitivities. The mutation-specific protein-protein interaction (PPI) networks underlying the differences, however, remain largely unexplored. In this study, we established experimental approaches to identify proteins in proximity to oncogenic PI3K using biotin ligase-based proximity labeling. Our data revealed that the PIK3CA H1047R and E545K mutants fused to BioID2 formed structurally distinct complexes, each associating with unique proximal proteins identified by liquid chromatography-tandem mass spectrometry. Further integration of the PPI networks with CRISPR dependency screens and multiomic profiling mapped the divergent functional interactomes of p110α hotspot mutants. H1047R exhibited a synthetic lethal dependency on the adaptor protein TAB2, which is associated with aggressive clinical phenotypes in breast cancer. Distinctly, E545K interacted with core subunits of the SWI/SNF chromatin remodeling complex, corresponding to a globally repressive chromatin state at distal enhancers. This SWI/SNF association also revealed a mutation-specific epigenetic vulnerability, with E545K-mutant cells displaying increased sensitivity to EZH2 inhibitors. Collectively, these findings demonstrate that the molecular network complexity of oncogenic PI3K can be interrogated through proximity labeling and that distinct PIK3CA point mutations rewire non-overlapping PPI networks, revealing domain-specific dependencies. Our study provides a framework for mapping mutation-specific interactomes and offers molecular insights and potential therapeutic strategies for PIK3CA-mutant tumors.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113655"},"PeriodicalIF":4.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Structural and Functional Characterization of a Novel Broad-Spectrum Oligosaccharide Uptake Channel OmpV25 in Vibrio campbellii. 坎贝尔弧菌新型广谱寡糖摄取通道OmpV25的结构和功能表征。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-16 DOI: 10.1016/j.jbc.2026.113656

Piyaporn Meesrikaew, H Sasimali M Soysa, Bundit Boonyarit, Albert Schulte, Robert C Robinson, Wipa Suginta

{"title":"Structural and Functional Characterization of a Novel Broad-Spectrum Oligosaccharide Uptake Channel OmpV25 in Vibrio campbellii.","authors":"Piyaporn Meesrikaew, H Sasimali M Soysa, Bundit Boonyarit, Albert Schulte, Robert C Robinson, Wipa Suginta","doi":"10.1016/j.jbc.2026.113656","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113656","url":null,"abstract":"Vibrio campbellii (formerly Vibrio harveyi) is a marine pathogen that causes vibriosis, a major disease affecting global aquaculture. This bacterium inhabits chitin-rich environments and uses chito-oligosaccharides as a main nutrient source. Here, we identify the novel outer membrane protein OmpV25 as a porin mediating broad-spectrum oligosaccharide uptake in V. campbellii. OmpV25 was heterologously expressed in Escherichia coli BL21 (DE3) Omp8, purified by nickel affinity and size exclusion chromatography, and crystallized. The resulting 2.70 Å crystal structure revealed the 25-kDa OmpV25 to be a monomeric β-barrel composed of 12 β-strands connected by six extracellular loops and five periplasmic turns. Single-channel electrophysiology demonstrated that OmpV25 forms stable monomeric pores in artificial lipid bilayers characterized by a conductance of 0.19 ± 0.003 nS in 1 M KCl. The channel facilitated binding of mono-, di-, tri- and tetragalacturonic acids, as well as chitotetraose and maltotetraose. Fluorescence spectroscopy revealed moderate-affinity binding to tetragalacturonic acid (Kd = 3.04 ± 0.42 μM), chitotetraose (Kd = 6.79 ± 0.27 μM), and maltotetraose (Kd = 5.21 ± 0.78 μM). A liposome swelling assay confirmed that OmpV25 enables translocation of a broad range of oligosaccharides beyond oligogalacturonic acids. These findings define the physiological role of OmpV25 as a broad-specificity sugar channel that may support environmental resilience of Vibrio species in nutrient-variable marine habitats.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113656"},"PeriodicalIF":4.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Suppression of Loss of the FabH 3-Ketoacyl-ACP Synthase III by a KAS II (FabF) Lacking the Active Site Thiol in Enterococcus faecalis. 缺乏活性位点硫醇的KAS II （FabF）抑制粪肠球菌中FabH 3-酮酰基- acp合成酶III的丧失

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-16 DOI: 10.1016/j.jbc.2026.113654

Huijuan Dong, John E Cronan

{"title":"Suppression of Loss of the FabH 3-Ketoacyl-ACP Synthase III by a KAS II (FabF) Lacking the Active Site Thiol in Enterococcus faecalis.","authors":"Huijuan Dong, John E Cronan","doi":"10.1016/j.jbc.2026.113654","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113654","url":null,"abstract":"The Enterococcus faecalis fabH gene encodes the sole 3-ketoacyl-ACP synthase III of the bacterium. FabH is a conserved enzyme in bacteria and chloroplasts responsible for initiation of bacterial fatty acid synthesis. FabH enzymes generally synthesize only short chain primers (C4-C6) which are elongated to the C16 and C18 chains of bacterial phospholipids by the long chain 3-ketoacyl-ACP synthases. The long chain enzymes are classed into types I and II depending on the ability of type I enzymes to perform an early step in unsaturated acyl chain synthesis. Like the paradigm E. coli pathway, E. faecalis has two long chain 3-ketoacyl-ACP synthases of types I and II, called FabO and FabF, respectively. Deletion of the E. faecalis fabH gene (ΔfabH) results in strains requiring an unsaturated fatty acid (e.g., oleic acid) for growth and almost complete loss of fatty acid synthesis. Upon plating on a medium of limiting fatty acid content, a few large suppressor colonies appeared on a lawn of tiny colonies. The suppressor strains were found to encode mutations in the FabF long chain acyl-ACP synthase II. Strikingly, in the fabF genes of the four suppressor strains a phenylalanine codon replaced the codon of the FabF active site cysteine, C162. Since the cysteine thiol is the key active site nucleophile of 3-ketoacyl-ACP synthases, the FabF(C162F) mutant proteins lacked KAS activity. The ability of the FabF(C162F) protein to bypass loss of FabH in vivo depended on expression of a functional FabO, the other long chain KAS I. We report that suppression of lack of FabH is due to acyl-ACP primer synthesis by the FabF(C162F) protein which catalyzes transfer of the acetyl moiety of acetyl-CoA to ACP dependent on histidine H301 of the FabF(C162F) protein. The acetyl-ACP primer is utilized by FabO, to synthesize the phospholipid acyl chains required for growth of the ΔfabH strain in the absence of fatty acid supplementation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113654"},"PeriodicalIF":4.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Roles of sialoglycans in vertebrate development. 唾液聚糖在脊椎动物发育中的作用。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-14 DOI: 10.1016/j.jbc.2026.113650

Herbert Hildebrandt, Anja Münster-Kühnel

{"title":"Roles of sialoglycans in vertebrate development.","authors":"Herbert Hildebrandt, Anja Münster-Kühnel","doi":"10.1016/j.jbc.2026.113650","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113650","url":null,"abstract":"In vertebrates, sialic acids are the terminal sugars of many glycan structures presented by glycolipids, glycoproteins and proteoglycans on the cell surface, in the extracellular matrix, and in bodily fluids. Due to their negative charge, they shape molecular interactions between cells as well as interactions with and within the microenvironment. Strategies to study the numerous and diverse functions of sialoglycans in health and disease range from global sialic acid deletions to the targeting of specific sialoglycan biosynthesis pathways in individual cell types or organs. Some of these approaches reveal fundamental, some rather subtle, or no developmental functions of specific sialoglycans. However, many of the available models aim to investigate selected aspects such as immune cell or tumor development (to name just two prominent examples), and most sialylation pathways remain severely understudied. Despite many excellent reviews on specific pathways, molecular entities, or disease- and organ-specific functions (as, e.g., assembled in this thematic series on sialic acids) a comprehensive current overview of the developmental roles of sialoglycans seems to be missing. This review tries to close this gap, but in light of the expert coverage of sialylated glycosphingolipids (gangliosides) in this series (1), we focus on the insights into the developmental roles of sialoglycans gained by approaches targeting sialylation per se or pathways affecting sialylation of either specifically glycoproteins or glycoproteins and glycolipids alike. In addition to the consequences of manipulations of global sialylation, particular emphasis will be on the developmental roles of polysialic acid in the brain and other organs.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113650"},"PeriodicalIF":4.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Liang-Wang syndrome-associated variants in the BK potassium channel KCNMA1 disrupt channel trafficking and gating. BK钾通道KCNMA1的Liang-Wang综合征相关变异破坏通道运输和门控。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-14 DOI: 10.1016/j.jbc.2026.113647

Chi Zhang, Nina-Maria Wilpert, Tie Ke, Hui Li, Chengqi Xu, Yufeng Yao, Qing K Wang

{"title":"Liang-Wang syndrome-associated variants in the BK potassium channel KCNMA1 disrupt channel trafficking and gating.","authors":"Chi Zhang, Nina-Maria Wilpert, Tie Ke, Hui Li, Chengqi Xu, Yufeng Yao, Qing K Wang","doi":"10.1016/j.jbc.2026.113647","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113647","url":null,"abstract":"Liang-Wang syndrome is a neurodevelopmental syndrome characterized by developmental delay and intellectual disability with variable multi-organ abnormalities, and caused by pathogenic variants in KCNMA1 encoding the BK potassium channel. In this study, we identified and characterized three new KCNMA1 variants, including p.W268R, p.A664T and p.M578T, for their molecular mechanism underlying the pathogenesis of Liang-Wang syndrome using macroscopic and single-channel patch-clamping recordings. We also evaluated the effects of BK channel activator NS11021 on the three variants. The three variants act by a loss-of-function mechanism (LOF) as all significantly reduced the macroscopic BK current densities by shifting the G-V curves to more positive potentials, increasing activation time constants, and decreasing single channel open probability. However, the detailed mechanisms are different. Variant p.W268R reduced BK channel trafficking to membranes, and reduced calcium and magnesium sensitivity; p.A664T decreased single channel open dwell time, reduced calcium sensitivity, but increased magnesium sensitivity; p.M578T decreased single channel open dwell time, and reduced calcium and magnesium sensitivity. Notably, NS11021 reversed the electrophysiological abnormalities associated with three KCNMA1 variants. In conclusion, our results provide important input for genetic testing and counseling, and show that small molecule compound NS11021 reverses cellular abnormalities associated with three Liang-Wang syndrome variants, suggesting a candidate therapeutic strategy.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113647"},"PeriodicalIF":4.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ERK-mediated phosphorylation modulates the autolytic processing of the cysteine protease CAPN3. erk介导的磷酸化调节半胱氨酸蛋白酶CAPN3的自溶过程。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-14 DOI: 10.1016/j.jbc.2026.113638

Chihiro Hisatsune, Fumiko Shinkai-Ouchi, Mayumi Shindo, Shoji Hata, Yasuko Ono

{"title":"ERK-mediated phosphorylation modulates the autolytic processing of the cysteine protease CAPN3.","authors":"Chihiro Hisatsune, Fumiko Shinkai-Ouchi, Mayumi Shindo, Shoji Hata, Yasuko Ono","doi":"10.1016/j.jbc.2026.113638","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113638","url":null,"abstract":"Calpain-3 (CAPN3) is a Ca2+-dependent cysteine protease predominantly expressed in skeletal muscles. Mutations in CAPN3 are associated with limb girdle muscular dystrophy R1 (LGMDR1), an autosomal recessive muscular dystrophy. CAPN3 is uniquely activated by rapid autolytic processing; however, the mechanisms regulating this activation are poorly understood. Here we show that phosphorylation regulates CAPN3 autolytic processing in living cells. We found that ouabain, a cardiac glycoside, activated ERK, which induced the phosphorylation of CAPN3 at S19 located within its N-terminal region. This phosphorylation promoted the N-terminal cleavage without altering the autolytic insertion sequence 1 (IS1) processing of CAPN3 or its subcellular localization in skeletal muscle cells. Notably, treatment of cultured skeletal muscle cells with insulin-like growth factor I (IGF-I), which can activate the ERK pathway, also induced S19 phosphorylation, suggesting that this modification can occur downstream of physiologically relevant extracellular signaling. These results demonstrate that ERK-mediated phosphorylation provides a regulatory mechanism for modulating N-terminal processing of CAPN3 without substantially affecting IS1 autolytic processing.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113638"},"PeriodicalIF":4.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Short-term methionine starvation reshapes diurnal hepatic m6A RNA methylation. 短期蛋氨酸饥饿重塑肝脏m6A RNA甲基化。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-14 DOI: 10.1016/j.jbc.2026.113645

Yang Liu, Kaliopi Chrysovergis, Katina L Johnson, Jason G Williams, Fred B Lih, Leesa J Deterding, Paul A Wade

{"title":"Short-term methionine starvation reshapes diurnal hepatic m6A RNA methylation.","authors":"Yang Liu, Kaliopi Chrysovergis, Katina L Johnson, Jason G Williams, Fred B Lih, Leesa J Deterding, Paul A Wade","doi":"10.1016/j.jbc.2026.113645","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113645","url":null,"abstract":"Dietary methionine restriction improves metabolic health and has therapeutic potential in multiple disease contexts. Methionine metabolism regulates transmethylation reactions, including N6-methyladenosine (m6A) RNA methylation, by modulating availability of S-adenosyl methionine (SAM). Both m6A methylation and methionine metabolism have separately been linked to circadian regulation, but whether dietary methionine influences circadian rhythms through m6A remains unknown. Here we show that short-term methionine deprivation induces diurnal variation in serum methionine and SAM and reprograms diurnal expression of m6A writers, erasers, and readers in mouse liver. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) at two timepoints (ZT9, ZT21) revealed that a methionine-deficient (MD) diet was associated with a roughly 10-fold increase in differentially methylated m6A peaks between timepoints relative to control, despite no change in methylation at core clock transcripts. These diet-induced oscillations arose at sites already methylated under the control diet, indicating that methionine restriction alters the rhythmicity of existing m6A marks rather than inducing new methylation, and were enriched in transcripts involved in RNA processing, translation, ubiquitination, and mTORC1 signaling. Integrating RNA-seq and proteomics, we found that a subset of these m6A changes co-occurred with altered mRNA and/or protein abundance, indicating gene-specific rather than global effects. Notably, reduced m6A methylation of Mat2a and Cbs, encoding enzymes central to methionine homeostasis, was associated with increased MAT2A and decreased CBS protein levels, respectively. These findings identify diet-induced, diurnally rhythmic m6A methylation as a candidate mechanism linking methionine metabolism to circadian biology and nominate specific m6A sites and pathways for future investigation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113645"},"PeriodicalIF":4.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The malonyl-CoA synthetase ACSF3 is required for metabolic editing downstream of biotin carboxylation. 丙二酰辅酶a合成酶ACSF3是生物素羧化下游代谢编辑所必需的。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-14 DOI: 10.1016/j.jbc.2026.113648

Joseph Choi, Jasmine Encarnacion, Daria Kurganova, Susanna Scafidi, Michael J Wolfgang

{"title":"The malonyl-CoA synthetase ACSF3 is required for metabolic editing downstream of biotin carboxylation.","authors":"Joseph Choi, Jasmine Encarnacion, Daria Kurganova, Susanna Scafidi, Michael J Wolfgang","doi":"10.1016/j.jbc.2026.113648","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113648","url":null,"abstract":"Acsf3, a mitochondrial malonyl-CoA synthetase, is mutated in the human inborn error Combined Malonic and Methylmalonic Aciduria. To clarify its role in mammalian metabolism, we generated Acsf3 knockout mice. We show that the loss of Acsf3 results in high concentrations of malonate and methylmalonate and exhibit expected defects in mitochondrial metabolism, but the KO mice are largely healthy similar to the human inborn error. Acsf3 KO mice exhibit redundancy in malonyl-CoA synthetase activity suggesting a genetic modifier of disease severity. Malonate and methylmalonate are metabolic poisons generated as a by-product of biotin dependent carboxylation that require metabolic editing. Indeed, the liver-specific loss of the biotin ligase, Holocarboxylase Synthetase (hlcs), inhibits all biotin dependent carboxylation and results in broad changes in liver mRNA, protein, posttranslational and metabolic regulation. Loss of Hlcs suppresses the metabolic deficits in Acsf3KO liver due to the inhibition of malonate and methylmalonate generation. Mice with a double knockout of Acsf3 and Hlcs maintained mitochondrial lipoylation demonstrating the highly redundant generation of mitochondrial malonyl-CoA. These data define the role of Acsf3 in metabolic editing of malonate and methylmalonate to maintain mitochondrial metabolism in the face of endogenously produced anti-metabolites.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113648"},"PeriodicalIF":4.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0