Journal of Biological Chemistry最新文献_第7页

Structural basis for L-isoaspartyl-containing protein recognition by the human PCMTD1 cullin-RING E3 ubiquitin ligase. 人PCMTD1 cullin-RING E3泛素连接酶识别含l-异天冬氨酸蛋白的结构基础。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-18 DOI: 10.1016/j.jbc.2025.110735

Eric Z Pang, Boyu Zhao, Cameron Flowers, Elizabeth Oroudjeva, Jasmine B Winter, Vijaya Pandey, Michael R Sawaya, James Wohlschlegel, Joseph A Loo, Jose A Rodriguez, Steven G Clarke

{"title":"Structural basis for L-isoaspartyl-containing protein recognition by the human PCMTD1 cullin-RING E3 ubiquitin ligase.","authors":"Eric Z Pang, Boyu Zhao, Cameron Flowers, Elizabeth Oroudjeva, Jasmine B Winter, Vijaya Pandey, Michael R Sawaya, James Wohlschlegel, Joseph A Loo, Jose A Rodriguez, Steven G Clarke","doi":"10.1016/j.jbc.2025.110735","DOIUrl":"10.1016/j.jbc.2025.110735","url":null,"abstract":"A major type of spontaneous protein damage that accumulates with age is the formation of kinked polypeptide chains with L-isoaspartyl residues. Mitigating this damage is necessary for maintaining proteome stability and prolonging organismal survival. While repair through methylation by PCMT1 has been previously shown to suppress L-isoaspartyl accumulation, we provide an additional mechanism for L-isoaspartyl maintenance through PCMTD1, a cullin-RING ligase (CRL). We combined cryo-EM, native mass spectrometry, and biochemical assays to provide insight on how the assembly and architecture of human PCMTD1 in the context of a CRL complex fulfils this alternative mechanism. We show that the PCMTD1 CRL complex specifically binds L-isoaspartyl residues when bound to AdoMet. This work provides evidence for a growing class of E3 ubiquitin ligases that recognize spontaneous covalent modifications as potential substrates for ubiquitylation and subsequent proteasomal degradation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110735"},"PeriodicalIF":4.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102730","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 ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy. 泛素结合蛋白ANKRD13A在PINK1/ parkin介导的线粒体自噬过程中介导vcp依赖的线粒体外膜破裂。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-18 DOI: 10.1016/j.jbc.2025.110739

Wei-Hua Chu,Yu-Shan Lin,Jing Guo,Wann-Neng Jane,Wong-Jing Wang,Yu-Yang Lin,Pei-Han Liu,Po-Yu Huang,Wei-Chung Chiang

{"title":"The ubiquitin-binding protein ANKRD13A mediates VCP-dependent mitochondrial outer membrane rupture during PINK1/Parkin-mediated mitophagy.","authors":"Wei-Hua Chu,Yu-Shan Lin,Jing Guo,Wann-Neng Jane,Wong-Jing Wang,Yu-Yang Lin,Pei-Han Liu,Po-Yu Huang,Wei-Chung Chiang","doi":"10.1016/j.jbc.2025.110739","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110739","url":null,"abstract":"PINK1/Parkin-mediated mitophagy is a major homeostatic mechanism by which cells selectively remove damaged, depolarized mitochondria. A signature event in this form of mitophagy is the rupture of the mitochondrial outer membrane (OMM), a process required for the proper disposal of the damaged, depolarized mitochondria. The OMM rupture results in the topological exposure of mitochondrial inner membrane (IMM) mitophagy receptors, which are recognized by autophagy machinery, thus promoting the turnover of the depolarized mitochondria. However, due to the lack of efficient tools to measure OMM rupture, our mechanistic understanding of this process has been limited. In this study, we identified ANKRD13A as a novel mitophagy factor that interacts with multiple mitochondrial proteins and re-localizes to the depolarized mitochondria. ANKRD13A promotes PINK1/Parkin-mediated mitophagy by recruiting Valosin-containing protein (VCP), an AAA-ATPase that functions to remodel protein complexes or membranes via the extraction of protein substrates. Through the development of a novel biosensor that fluorescently marks the sites of OMM rupture, we visualized the OMM rupture events in cellulo and revealed that VCP and its recruitment factors, including ANKRD13A, are required for the rupture of OMM. This finding demonstrated that VCP-dependent remodeling of OMM during PINK1/Parkin-mediated mitophagy is a key driving force behind the OMM rupture. Furthermore, our newly developed biosensor represents an effective, reliable method to detect OMM rupture during PINK1/Parkin-mediated mitophagy, and it is valuable for future mechanistic investigation of this process.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"8 1","pages":"110739"},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093559","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 ubiquitin ligase Nedd4-2 promotes localization of DNMBP/Tuba to P-bodies under hyperosmotic stress. 在高渗胁迫下，泛素连接酶Nedd4-2促进DNMBP/Tuba向p体的定位。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-18 DOI: 10.1016/j.jbc.2025.110738

Zetao Liu,Chong Jiang,Faith Yeung,Brian Raught,Daniela Rotin

{"title":"The ubiquitin ligase Nedd4-2 promotes localization of DNMBP/Tuba to P-bodies under hyperosmotic stress.","authors":"Zetao Liu,Chong Jiang,Faith Yeung,Brian Raught,Daniela Rotin","doi":"10.1016/j.jbc.2025.110738","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110738","url":null,"abstract":"The ubiquitin ligase Nedd4-2/NEDD4L, comprised of C2-WW(x4)-HECT domains, is known to regulate several ion transporters and channels. We recently showed that elevated intracellular [Na+] and osmolarity enhances Nedd4-2 enzymatic activity. To globally identify its interactome and substrates in cells under hyperosmotic stress, we performed a BioID screen using miniTurbo with Nedd4-2 as a bait under hyperosmotic (vs. isosmotic) conditions. One of the top hits identified that preferentially binds Nedd4-2 under hyperosmolarity was Dynamin-Binding-Protein (DNMBP)/Tuba, a known GEF for Cdc42. We then showed that DNMBP is a substrate for Nedd4-2, and that active Nedd4-2 targets DNMBP to P-body condensates under hyperosmotic stress. Moreover, DNMBP itself promotes P-body formation under hyperosmolarity. Both Nedd4-2 and DNMBP are required for the activation of Cdc42 following hyperosmotic treatment, and accordingly, knockout of DNMBP results in suppression of Cdc42 and its downstream effector p38-MAPK. We thus propose that Nedd4-2 - mediated targeting of DNMBP to P-bodies under hyperosmotic stress facilitates the activation of Cdc42 by this GEF.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"80 1","pages":"110738"},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093561","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

SA-XV, a 15-amino acid fragment of host defense peptide S100A12, targets mitochondria, and is protective against fungal infections. SA-XV是宿主防御肽S100A12的一个15个氨基酸片段，靶向线粒体，并对真菌感染具有保护作用。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-18 DOI: 10.1016/j.jbc.2025.110743

Riddhi Agarwal,Karishma Biswas,Akshita Agrawal,Nisha Nandhini Shankar,Srijita Kundu,Dipanwita Roy,DoekHyun Son,Amaravadhi Harikishore,Ragothaman M Yennamalli,DongKuk Lee,Anirban Bhunia,Sanhita Roy

{"title":"SA-XV, a 15-amino acid fragment of host defense peptide S100A12, targets mitochondria, and is protective against fungal infections.","authors":"Riddhi Agarwal,Karishma Biswas,Akshita Agrawal,Nisha Nandhini Shankar,Srijita Kundu,Dipanwita Roy,DoekHyun Son,Amaravadhi Harikishore,Ragothaman M Yennamalli,DongKuk Lee,Anirban Bhunia,Sanhita Roy","doi":"10.1016/j.jbc.2025.110743","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110743","url":null,"abstract":"Fungal infections are huge emerging crisis with more than two million people infected worldwide annually. Corneal infections caused by fungus is the major cause of vision loss and often warrants corneal transplantation. Both Fusarium spp. and Candida spp. are critical etiological agents of fungal keratitis and also common cause for invasive fungal infections with high mortality rates. In previous work we described growth inhibition of Fusarium spp. by S100A12, a host antimicrobial peptide. Here, to optimize a potential therapeutic, we have studied a 15 amino acid fragment of S100A12, SA-XV. Interestingly, SA-XV demonstrated remarkable antifungal activities, similar to the parent peptide, against both Fusarium spp. and Candida spp. SA-XV is a cell penetrating peptide, and once internalized, it binds to fungal DNA, halts cell cycle, and disrupts mitochondria leading to generation of reactive oxygen species and cell damage. Atomistic structure of the peptide determined by NMR reveals that SA-XV associates with fungal membrane. The structural changes in SA-XV from α-helical to random coil conformation was observed in all-atom simulations. Additionally, SA-XV aids in wound healing of corneal epithelial cells and attenuate the fungal burden in a murine model of fungal keratitis. Our results clearly demonstrate SA-XV as a promising antifungal candidate that targets both filamentous and non-filamentous fungus for alternative therapeutic interventions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"18 1","pages":"110743"},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093566","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

Compartmentalized thymidine phosphorylation by mitochondrial nucleotide kinases TK2 and CMPK2. 线粒体核苷酸激酶TK2和CMPK2的区隔化胸腺嘧啶磷酸化。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-16 DOI: 10.1016/j.jbc.2025.110733

Avery S Ward,Vasudeva G Kamath,Chia-Heng Hsiung,Zachary J Lizenby,Alexander G Gillish,D Stave Kohtz,Edward E McKee

{"title":"Compartmentalized thymidine phosphorylation by mitochondrial nucleotide kinases TK2 and CMPK2.","authors":"Avery S Ward,Vasudeva G Kamath,Chia-Heng Hsiung,Zachary J Lizenby,Alexander G Gillish,D Stave Kohtz,Edward E McKee","doi":"10.1016/j.jbc.2025.110733","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110733","url":null,"abstract":"Deoxynucleotides (dNTPs) in post-mitotic tissues rely on deoxynucleoside salvage pathways in order to repair and replicate nuclear and mitochondrial DNA (mtDNA). Previous work from our laboratory showed in perfused rat heart and isolated mitochondria that the only substrate for TTP synthesis is thymidine. When thymidylate (TMP) is provided to bypass thymidine kinase 2 (TK2) the substrate is readily dephosphorylated to thymidine before salvage occurs suggesting compartmentalization within the heart mitochondrial matrix. The goal of this work extends these findings in the heart to mitochondria from other post-mitotic tissues, including rat liver, kidney, and brain. Using AZT to block mitochondrial thymidine kinase 2, we demonstrate that TMP cannot serve as a precursor for TTP synthesis in isolated mitochondria from any of these tissues unless it is de-phosphorylated to thymidine first. Broken mitochondria incubated with labeled TMP showed similar results as intact mitochondria, suggesting the findings are not related to TMP transport across the inner mitochondrial membrane. Further, using proximity labeling with immunofluorescence microscopy we provide evidence supporting the hypothesis that TMP compartmentation is accounted for by the interaction of TK2 and CMPK2 in the mitochondria. Differential fraction experiments provide additional evidence that association with TK2 allows CMPK2 to display TMPK2 activity. Together, the results indicate that a two-step phosphorylation of thymidine to TDP occurs because the proximity of TK2 and CMPK2 in the mitochondria prevents TMP from diffusing from the two enzymes.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"56 1","pages":"110733"},"PeriodicalIF":4.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083552","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

An amino acid transporter in the small intestine mediates basolateral efflux of plant-derived nicotianamine iron complexes. 小肠中的氨基酸转运体介导植物源性烟胺铁复合物的基底外侧外排。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-16 DOI: 10.1016/j.jbc.2025.110731

Yoshiko Murata,Makoto Fujisawa,Takehiro Watanabe,Shin Matsubara,Yuta Takase,Toshio Takahashi,Kosuke Namba,Atsushi Yamagata,Tohru Terada

{"title":"An amino acid transporter in the small intestine mediates basolateral efflux of plant-derived nicotianamine iron complexes.","authors":"Yoshiko Murata,Makoto Fujisawa,Takehiro Watanabe,Shin Matsubara,Yuta Takase,Toshio Takahashi,Kosuke Namba,Atsushi Yamagata,Tohru Terada","doi":"10.1016/j.jbc.2025.110731","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110731","url":null,"abstract":"Nicotianamine (NA), a plant-derived metal chelator abundant in vegetables, is a bioavailable iron-chelating compound in mammals. We recently reported that NA-iron (NA-Fe) complexes are absorbed in the small intestine via a proton-conjugated amino acid transporter (PAT1). However, the subsequent process remains unknown. In this study, using radioactive iron tracers and NA export quantification in Xenopus laevis oocytes, we identified the heterodimeric amino acid transporter as being responsible for transporting NA-Fe(II) complexes into the vascular system; this complex is composed of L-type amino acid transporter 2 (LAT2) and 4F2 heavy chain (4F2hc). Oocytes expressing LAT2/4F2hc exhibited significantly higher efflux of NA-59Fe(II) than free Fe via ferroportin 1, indicating an NA-Fe(II)-specific excretion mechanism. A LAT2 mutant (N134S), which is known to enhance amino acid efflux, also increased radioactive iron-NA excretion. Molecular modeling revealed that the substrate-binding cavity of LAT2 could accommodate NA-Fe(II), suggesting that NA-Fe(II) could be transported through the same cavity entrance as amino acids. The expression profiles of PAT1 and LAT2/4F2hc in the small intestine were higher in the proximal jejunum than in the duodenum, which was consistent with the NA and iron content profiles in the small intestine of mice treated with NA-Fe(II). These findings suggest the presence of different iron absorption mechanisms. Iron is directly absorbed in the duodenum via the divalent metal transporter 1/ferroportin 1 system and as an iron-chelator complex in the proximal jejunum via the PAT1/LAT2(4F2hc) amino acid transporter system.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"6 1","pages":"110731"},"PeriodicalIF":4.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083549","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

Reconstituted ferredoxin-MEP pathway of Apicomplexa in E. coli as an in situ screening platform for inhibitors and essential enzyme mutations. 重组大肠杆菌顶复合体的铁氧化还原蛋白- mep通路，作为抑制剂和必需酶突变的原位筛选平台。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-16 DOI: 10.1016/j.jbc.2025.110726

Ojo-Ajogu Akuh,Deborah Maus,Martin Blume,Kevin J Saliba,Frank Seeber

{"title":"Reconstituted ferredoxin-MEP pathway of Apicomplexa in E. coli as an in situ screening platform for inhibitors and essential enzyme mutations.","authors":"Ojo-Ajogu Akuh,Deborah Maus,Martin Blume,Kevin J Saliba,Frank Seeber","doi":"10.1016/j.jbc.2025.110726","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110726","url":null,"abstract":"The apicoplast, an essential plastid-like organelle of apicomplexan parasites, including Plasmodium spp. and Toxoplasma gondii, harbors unique metabolic pathways absent in the host. Within the apicoplast, the ferredoxin redox system consists of plant-type ferredoxin-NADP+ reductase (ptFNR) and its redox partner, plant-type ferredoxin (ptFd). It donates electrons to the last two enzymes in the essential methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis. To establish an easy-to-handle platform for screening for enzyme inhibitors or functional mutations of the P. falciparum MEP pathway in situ, we established an E. coli model where bacterial growth depended on the last enzyme IspH and its redox system ptFd and ptFNR. For this, we supplemented a flavodoxin and ispH E. coli double mutant with expression constructs for ptFd, ptFNR, and IspH from P. falciparum. These proteins could functionally replace the two essential endogenous E. coli enzymes, reconstituting the last step in the isoprenoid biosynthesis pathway of the apicoplast. To validate this strain as a screening platform we used point mutations in ptFd as a surrogate for chemical pathway inhibitors. Several single mutants were evaluated by growth assays to identify amino acids that are essential for proliferation. We verified the mutants' consequences on the depletion of MEP metabolites by LC-MS analysis. Finally, some mutants were used to complement a conditional T. gondii Fd knockout strain. The results mirrored those of the respective E. coli mutant, highlighting the model's utility in identifying functional mutations or ptFd/MEP pathway inhibitors before conducting more labor-intensive and time-consuming assays in parasites.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"63 1","pages":"110726"},"PeriodicalIF":4.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083551","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

Kinetic mechanisms of electron bifurcation with electron transfer flavoprotein, NADH, butyryl-CoA dehydrogenase, and ferredoxin reveal a semiquinone cycle. 电子转移黄蛋白、NADH、丁基辅酶a脱氢酶和铁氧还蛋白的电子分岔动力学机制揭示了一个半醌循环。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-16 DOI: 10.1016/j.jbc.2025.110727

Jeerus Sucharitakul,Montisa Mangkalee,Pattarawan Intasian,Soraya Pornsuwan,Ulrich Ermler,Wolfgang Buckel,Pimchai Chaiyen

{"title":"Kinetic mechanisms of electron bifurcation with electron transfer flavoprotein, NADH, butyryl-CoA dehydrogenase, and ferredoxin reveal a semiquinone cycle.","authors":"Jeerus Sucharitakul,Montisa Mangkalee,Pattarawan Intasian,Soraya Pornsuwan,Ulrich Ermler,Wolfgang Buckel,Pimchai Chaiyen","doi":"10.1016/j.jbc.2025.110727","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110727","url":null,"abstract":"Electron transfer flavoprotein (EtfAB, with α-FAD and β-FAD) and tetrameric butyryl-CoA dehydrogenase (Bcd, with δ-FAD in each subunit) from Acidaminococcus fermentans catalyze electron bifurcation which reduces low potential ferredoxin (Fd) and high potential crotonyl-CoA using NADH as an electron donor. Our previous rapid kinetic studies have demonstrated \"pseudo-electron bifurcation\" where NADH and two EtfAB molecules generate EtfASQB (ASQ = α-FAD●-) and the charge-transfer complex of EtfASQBHQ:NAD+ (BHQ = β-FADH-). Since the radical in EtfASQB inhibits the further reduction of β-FAD with NADH, the question arises as to how the five components of the complete system interact to mediate the whole flavin-based electron bifurcation. This study shows that Bcd releases the inhibition effect of α-FAD•-, allowing fast β-FAD reduction for turnover. In the presence of both Bcd and Fd, the total β-FADH- of EtfAB bifurcates to afford α-FAD●- and Fd-; a second bifurcation yields α-FADH- in the Bcd-EtfAHQB complex and additional Fd-. In the presence of crotonyl-CoA, two simultaneous one-electron transfers from both EtfAHQB yield reduced Bcd and two EtfASQB, confirmed by EPR spectroscopy. This step is proposed to require a slow conformational change of the Bcd-EtfAB complex for electron transfer with a limiting rate constant of 0.0098 s-1 at 4 °C but increases about 14-fold to 0.14 s-1 at 30 °C, the optimal growth temperature of A. fermentans. The final reduction of crotonyl-CoA to butyryl-CoA completes the cycle, which we call the semiquinone cycle of electron bifurcation, because it starts and ends with a semiquinone.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"2 1","pages":"110727"},"PeriodicalIF":4.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083554","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

Inhibition of HDAC7 reprograms the histone H3.3 landscape to induce heterochromatin spreading and DNA replication defects in cancer cells. 抑制HDAC7重编程组蛋白H3.3景观，诱导癌细胞中异染色质扩散和DNA复制缺陷。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-16 DOI: 10.1016/j.jbc.2025.110732

Ola Hassan, Mattia Pizzagalli, Owen Leary, John P Zepecki, Adrianne Corseri, Laura Jinxuan Wu, Shiven Sasipalli, Daniel Lee, Lindsey Hayward, Lily Tran, Eduardo Fajardo, Andras Fiser, David Karambizi, Nikos Tapinos

{"title":"Inhibition of HDAC7 reprograms the histone H3.3 landscape to induce heterochromatin spreading and DNA replication defects in cancer cells.","authors":"Ola Hassan, Mattia Pizzagalli, Owen Leary, John P Zepecki, Adrianne Corseri, Laura Jinxuan Wu, Shiven Sasipalli, Daniel Lee, Lindsey Hayward, Lily Tran, Eduardo Fajardo, Andras Fiser, David Karambizi, Nikos Tapinos","doi":"10.1016/j.jbc.2025.110732","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110732","url":null,"abstract":"Class IIa histone deacetylases (HDACs) have minimal histone deacetylase activity but may function as multi-protein interaction hubs. Here, we demonstrated the expression of histone deacetylase 7 (HDAC7), a Class IIa HDAC family member, in glioblastoma tumor tissue from 84 patients, patient-derived glioma stem cells (GSCs) from six patients, and pediatric diffuse pontine glioma (DIPG) cells from three patients. HDAC7 binds to Histone H3.3 and interacts with H3.3 and HIRA on chromatin. Targeted downregulation of HDAC7 expression with a subtype-specific siRNA inhibits the interaction of H3.3 with HIRA, increasing the association of H3.3 with DAXX and H3K9me3, leading to H3.3 deposition on H3K9me3+/DAPI+ heterochromatin nuclear foci. HDAC7 inhibition triggers H3K9me3+ heterochromatin spreading, increased H3K9me3 binding in the cancer genome, and significant alterations in gene expression. Using single-molecule DNA fiber analysis, we showed that HDAC7 inhibition resulted in a significant increase in replication fork speed without affecting fork symmetry, leading to replication stress, phosphorylation RPA2 and reduced 5-ethynyl 2´-deoxyuridine (EdU) incorporation. HDAC7 depletion also reduces BRCA2 expression and increases cancer cell sensitivity to DNA-damaging agents. These findings reveal HDAC7's role in the euchromatic H3.3 chaperone network and the impact of HDAC7 depletion on chromatin dynamics, epigenetic restriction, and DNA damage in cancer cells.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110732"},"PeriodicalIF":4.0,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085989","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

Loss of TRIM44 promotes renal cell carcinoma progression by regulating K48-linked ubiquitination of vimentin. TRIM44的缺失通过调节k48相关的vimentin泛素化促进肾细胞癌的进展。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-16 DOI: 10.1016/j.jbc.2025.110734

Ke Shi,Baiyun Jia,Yuanyu Li,Xiaojuan Feng,Xusheng Sun,Qingjuan Liu,Wei Zhang,Yuexin Tian,Xinyan Miao,Yunhe Liu,Hang Zhao,Lihua Kang,Tongyu Zhao,Shiqi Zhang,Jinxi Liu,Shuxia Liu

{"title":"Loss of TRIM44 promotes renal cell carcinoma progression by regulating K48-linked ubiquitination of vimentin.","authors":"Ke Shi,Baiyun Jia,Yuanyu Li,Xiaojuan Feng,Xusheng Sun,Qingjuan Liu,Wei Zhang,Yuexin Tian,Xinyan Miao,Yunhe Liu,Hang Zhao,Lihua Kang,Tongyu Zhao,Shiqi Zhang,Jinxi Liu,Shuxia Liu","doi":"10.1016/j.jbc.2025.110734","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110734","url":null,"abstract":"Tripartite motif-containing 44 (TRIM44), a member of the TRIM protein family, has emerged as a regulator in multiple cancer types, yet its functional role and molecular mechanisms in clear cell renal cell carcinoma (ccRCC) remain poorly characterized. Here, we identified TRIM44 as a tumor suppressor in ccRCC through integrated clinical and functional analyses. Clinically, TRIM44 expression was significantly downregulated in ccRCC tissues compared with adjacent normal tissues, and its reduced expression correlated with advanced tumor stage and poor patient prognosis. Functionally, gain- and loss-of-function experiments demonstrated that TRIM44 potently inhibited ccRCC cell migration, invasion, and proliferation in vitro and in vivo. Mechanistically, TRIM44 directly interacts with vimentin. Importantly, we found that TRIM44 promotes K48-linked polyubiquitination of vimentin through its B-box domain, thereby targeting vimentin for proteasomal degradation. Collectively, our study establishes TRIM44 as a critical regulator of ccRCC progression through vimentin destabilization, highlighting its potential as both a prognostic biomarker and therapeutic target for ccRCC.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"68 1","pages":"110734"},"PeriodicalIF":4.8,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083548","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}

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