Biochemical Journal最新文献_第8页

Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice. 结肠酮体生成是一个受微生物群调控的过程，它有助于血液中酮体的生成并防止小鼠患结肠炎。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230403

Kevin Bass, Sathish Sivaprakasam, Gunadharini Dharmalingam-Nandagopal, Muthusamy Thangaraju, Vadivel Ganapathy

{"title":"Colonic ketogenesis, a microbiota-regulated process, contributes to blood ketones and protects against colitis in mice.","authors":"Kevin Bass, Sathish Sivaprakasam, Gunadharini Dharmalingam-Nandagopal, Muthusamy Thangaraju, Vadivel Ganapathy","doi":"10.1042/BCJ20230403","DOIUrl":"10.1042/BCJ20230403","url":null,"abstract":"Ketogenesis is considered to occur primarily in liver to generate ketones as an alternative energy source for non-hepatic tissues when glucose availability/utilization is impaired. 3-Hydroxy-3-methylglutaryl-CoA synthase-2 (HMGCS2) mediates the rate-limiting step in this mitochondrial pathway. Publicly available databases show marked down-regulation of HMGCS2 in colonic tissues in Crohn's disease and ulcerative colitis. This led us to investigate the expression and function of this pathway in colon and its relevance to colonic inflammation in mice. Hmgcs2 is expressed in cecum and colon. As global deletion of Hmgcs2 showed significant postnatal mortality, we used a conditional knockout mouse with enzyme deletion restricted to intestinal tract. These mice had no postnatal mortality. Fasting blood ketones were lower in these mice, indicating contribution of colonic ketogenesis to circulating ketones. There was also evidence of gut barrier breakdown and increased susceptibility to experimental colitis with associated elevated levels of IL-6, IL-1β, and TNF-α in circulation. Interestingly, many of these phenomena were mostly evident in male mice. Hmgcs2 expression in colon is controlled by colonic microbiota as evidenced from decreased expression in germ-free mice and antibiotic-treated conventional mice and from increased expression in a human colonic epithelial cell line upon treatment with aqueous extracts of cecal contents. Transcriptomic analysis of colonic epithelia from control mice and Hmgcs2-null mice indicated an essential role for colonic ketogenesis in the maintenance of optimal mitochondrial function, cholesterol homeostasis, and cell-cell tight-junction organization. These findings demonstrate a sex-dependent obligatory role for ketogenesis in protection against colonic inflammation in mice.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"481 4","pages":"295-312"},"PeriodicalIF":4.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903465/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899306","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Parkinson's disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress. 与帕金森病相关的突变体 VPS35 (D620N) 会放大 LRRK2 对溶酶体内压力的反应。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230492

Katy R McCarron, Hannah Elcocks, Heather Mortiboys, Sylvie Urbé, Michael J Clague

{"title":"The Parkinson's disease related mutant VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress.","authors":"Katy R McCarron, Hannah Elcocks, Heather Mortiboys, Sylvie Urbé, Michael J Clague","doi":"10.1042/BCJ20230492","DOIUrl":"10.1042/BCJ20230492","url":null,"abstract":"The identification of multiple genes linked to Parkinson's disease (PD) invites the question as to how they may co-operate. We have generated isogenic cell lines that inducibly express either wild-type or a mutant form of the retromer component VPS35 (D620N), which has been linked to PD. This has enabled us to test proposed effects of this mutation in a setting where the relative expression reflects the physiological occurrence. We confirm that this mutation compromises VPS35 association with the WASH complex, but find no defect in WASH recruitment to endosomes, nor in the distribution of lysosomal receptors, cation-independent mannose-6-phosphate receptor and Sortilin. We show VPS35 (D620N) enhances the activity of the Parkinson's associated kinase LRRK2 towards RAB12 under basal conditions. Furthermore, VPS35 (D620N) amplifies the LRRK2 response to endolysosomal stress resulting in enhanced phosphorylation of RABs 10 and 12. By comparing different types of endolysosomal stresses such as the ionophore nigericin and the membranolytic agent l-leucyl-l-leucine methyl ester, we are able to dissociate phospho-RAB accumulation from membrane rupture.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"265-278"},"PeriodicalIF":4.1,"publicationDate":"2024-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139650228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Beyond the tail: the consequence of context in histone post-translational modification and chromatin research. 超越尾巴：组蛋白翻译后修饰和染色质研究中的背景影响。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-21 DOI: 10.1042/BCJ20230342

Ellen N Weinzapfel, Karlie N Fedder-Semmes, Zu-Wen Sun, Michael-Christopher Keogh

引用次数: 0

The role of mitochondrial RNA association for mitochondrial homeostasis in neurons 线粒体 RNA 关联对神经元线粒体平衡的作用

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-02-07 DOI: 10.1042/bcj20230110

Segura, Inmaculada, Harbauer, Angelika

引用次数: 0

A highly conserved ligand-binding site for AccA transporters of antibiotic and quorum-sensing regulator in Agrobacterium leads to a different specificity. 在农杆菌中，抗生素和群体感应调节剂的AccA转运体的高度保守的配体结合位点导致了不同的特异性。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-01-25 DOI: 10.1042/BCJ20230273

Solange Moréra, Armelle Vigouroux, Magali Aumont-Nicaise, Mohammed Ahmar, Thibault Meyer, Abbas El Sahili, Grégory Deicsics, Almudena González-Mula, Sizhe Li, Jeanne Doré, Serena Sirigu, Pierre Legrand, Camille Penot, François André, Denis Faure, Laurent Soulère, Yves Queneau, Ludovic Vial

{"title":"A highly conserved ligand-binding site for AccA transporters of antibiotic and quorum-sensing regulator in Agrobacterium leads to a different specificity.","authors":"Solange Moréra, Armelle Vigouroux, Magali Aumont-Nicaise, Mohammed Ahmar, Thibault Meyer, Abbas El Sahili, Grégory Deicsics, Almudena González-Mula, Sizhe Li, Jeanne Doré, Serena Sirigu, Pierre Legrand, Camille Penot, François André, Denis Faure, Laurent Soulère, Yves Queneau, Ludovic Vial","doi":"10.1042/BCJ20230273","DOIUrl":"10.1042/BCJ20230273","url":null,"abstract":"Plants genetically modified by the pathogenic Agrobacterium strain C58 synthesize agrocinopines A and B, whereas those modified by the pathogenic strain Bo542 produce agrocinopines C and D. The four agrocinopines (A, B, C and D) serve as nutrients by agrobacteria and signaling molecule for the dissemination of virulence genes. They share the uncommon pyranose-2-phosphate motif, represented by the l-arabinopyranose moiety in agrocinopines A/B and the d-glucopyranose moiety in agrocinopines C/D, also found in the antibiotic agrocin 84. They are imported into agrobacterial cytoplasm via the Acc transport system, including the solute-binding protein AccA coupled to an ABC transporter. We have previously shown that unexpectedly, AccA from strain C58 (AccAC58) recognizes the pyranose-2-phosphate motif present in all four agrocinopines and agrocin 84, meaning that strain C58 is able to import agrocinopines C/D, originating from the competitor strain Bo542. Here, using agrocinopine derivatives and combining crystallography, affinity and stability measurements, modeling, molecular dynamics, in vitro and vivo assays, we show that AccABo542 and AccAC58 behave differently despite 75% sequence identity and a nearly identical ligand binding site. Indeed, strain Bo542 imports only compounds containing the d-glucopyranose-2-phosphate moiety, and with a lower affinity compared with strain C58. This difference in import efficiency makes C58 more competitive than Bo542 in culture media. We can now explain why Agrobacterium/Allorhizobium vitis strain S4 is insensitive to agrocin 84, although its genome contains a conserved Acc transport system. Overall, our work highlights AccA proteins as a case study, for which stability and dynamics drive specificity.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"93-117"},"PeriodicalIF":4.1,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138497730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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 mTORC2 signaling network: targets and cross-talks. mTORC2 信号网络：目标和交叉联系。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-01-25 DOI: 10.1042/BCJ20220325

Aparna Ragupathi, Christian Kim, Estela Jacinto

{"title":"The mTORC2 signaling network: targets and cross-talks.","authors":"Aparna Ragupathi, Christian Kim, Estela Jacinto","doi":"10.1042/BCJ20220325","DOIUrl":"10.1042/BCJ20220325","url":null,"abstract":"The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"481 2","pages":"45-91"},"PeriodicalIF":4.1,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903481/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139544917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The role of phosphorylation in calmodulin-mediated gating of human AQP0. 磷酸化在钙调素介导的人AQP0门控中的作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-01-10 DOI: 10.1042/BCJ20230158

Stefan Kreida, Jennifer Virginia Roche, Julie Winkel Missel, Tamim Al-Jubair, Carl Johan Hagströmer, Veronika Wittenbecher, Sara Linse, Pontus Gourdon, Susanna Törnroth-Horsefield

{"title":"The role of phosphorylation in calmodulin-mediated gating of human AQP0.","authors":"Stefan Kreida, Jennifer Virginia Roche, Julie Winkel Missel, Tamim Al-Jubair, Carl Johan Hagströmer, Veronika Wittenbecher, Sara Linse, Pontus Gourdon, Susanna Törnroth-Horsefield","doi":"10.1042/BCJ20230158","DOIUrl":"10.1042/BCJ20230158","url":null,"abstract":"Aquaporin-0 (AQP0) is the main water channel in the mammalian lens and is involved in accommodation and maintaining lens transparency. AQP0 binds the Ca2+-sensing protein calmodulin (CaM) and this interaction is believed to gate its water permeability by closing the water-conducting pore. Here, we express recombinant and functional human AQP0 in Pichia pastoris and investigate how phosphorylation affects the interaction with CaM in vitro as well as the CaM-dependent water permeability of AQP0 in proteoliposomes. Using microscale thermophoresis and surface plasmon resonance technology we show that the introduction of the single phospho-mimicking mutations S229D and S235D in AQP0 reduces CaM binding. In contrast, CaM interacts with S231D with similar affinity as wild type, but in a different manner. Permeability studies of wild-type AQP0 showed that the water conductance was significantly reduced by CaM in a Ca2+-dependent manner, whereas AQP0 S229D, S231D and S235D were all locked in an open state, insensitive to CaM. We propose a model in which phosphorylation of AQP0 control CaM-mediated gating in two different ways (1) phosphorylation of S229 or S235 abolishes binding (the pore remains open) and (2) phosphorylation of S231 results in CaM binding without causing pore closure, the functional role of which remains to be elucidated. Our results suggest that site-dependent phosphorylation of AQP0 dynamically controls its CaM-mediated gating. Since the level of phosphorylation increases towards the lens inner cortex, AQP0 may become insensitive to CaM-dependent gating along this axis.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":"17-32"},"PeriodicalIF":4.1,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138457614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proximity labelling reveals effects of disease-causing mutation on the DNAJC5/cysteine string protein α interactome. 近距离标记揭示了致病突变对DNAJC5/半胱氨酸串联蛋白α相互作用组的影响。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-01-09 DOI: 10.1042/BCJ20230319

Eleanor Barker, Amy Milburn, Nordine Helassa, Dean Hammond, Natalia Sanchez-Soriano, Alan Morgan, Jeff Barclay

{"title":"Proximity labelling reveals effects of disease-causing mutation on the DNAJC5/cysteine string protein α interactome.","authors":"Eleanor Barker, Amy Milburn, Nordine Helassa, Dean Hammond, Natalia Sanchez-Soriano, Alan Morgan, Jeff Barclay","doi":"10.1042/BCJ20230319","DOIUrl":"10.1042/BCJ20230319","url":null,"abstract":"Cysteine string protein α (CSPα), also known as DNAJC5, is a member of the DnaJ/Hsp40 family of co-chaperones. The name derives from a cysteine-rich domain, palmitoylation of which enables localization to intracellular membranes, notably neuronal synaptic vesicles. Mutations in the DNAJC5 gene that encodes CSPα cause autosomal dominant, adult-onset neuronal ceroid lipofuscinosis (ANCL), a rare neurodegenerative disease. As null mutations in CSP-encoding genes in flies, worms and mice similarly result in neurodegeneration, CSP is evidently an evolutionarily conserved neuroprotective protein. However, the client proteins that CSP chaperones to prevent neurodegeneration remain unclear. Traditional methods for identifying protein-protein interactions such as yeast 2-hybrid and affinity purification approaches are poorly suited to CSP, due to its requirement for membrane anchoring and its tendency to aggregate after cell lysis. Therefore, we employed proximity labelling, which enables identification of interacting proteins in situ in living cells via biotinylation. Neuroendocrine PC12 cell lines stably expressing wild type or L115R ANCL mutant CSP constructs fused to miniTurbo were generated; then the biotinylated proteomes were analysed by liquid chromatographymass spectrometry (LCMS) and validated by western blotting. This confirmed several known CSP-interacting proteins, such as Hsc70 and SNAP-25, but also revealed novel binding proteins, including STXBP1/Munc18-1. Interestingly, some protein interactions (such as Hsc70) were unaffected by the L115R mutation, whereas others (including SNAP-25 and STXBP1/Munc18-1) were inhibited. These results define the CSP interactome in a neuronal model cell line and reveal interactions that are affected by ANCL mutation and hence may contribute to the neurodegeneration seen in patients.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography. 利用低温电子断层扫描技术研究 ATP 合酶二聚体角度对线粒体形态的影响。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2024-01-02 DOI: 10.1042/BCJ20230450

Emma Buzzard, Mathew McLaren, Piotr Bragoszewski, Andrea Brancaccio, Holly Ford, Bertram Daum, Patricia Kuwabara, Ian Collinson, Vicki Gold

{"title":"The consequence of ATP synthase dimer angle on mitochondrial morphology studied by cryo-electron tomography.","authors":"Emma Buzzard, Mathew McLaren, Piotr Bragoszewski, Andrea Brancaccio, Holly Ford, Bertram Daum, Patricia Kuwabara, Ian Collinson, Vicki Gold","doi":"10.1042/BCJ20230450","DOIUrl":"10.1042/BCJ20230450","url":null,"abstract":"Mitochondrial ATP synthases form rows of dimers, which induce membrane curvature to give cristae their characteristic lamellar or tubular morphology. The angle formed between the central stalks of ATP synthase dimers varies between species. Using cryo-electron tomography and sub-tomogram averaging, we determined the structure of the ATP synthase dimer from the nematode worm C. elegans and show that the dimer angle differs from previously determined structures. The consequences of this species-specific difference at the dimer interface were investigated by comparing C. elegans and S. cerevisiae mitochondrial morphology. We reveal that C. elegans has a larger ATP synthase dimer angle with more lamellar (flatter) cristae when compared to yeast. The underlying cause of this difference was investigated by generating an atomic model of the C. elegans ATP synthase dimer by homology modelling. A comparison of our C. elegans model to an existing S. cerevisiae structure reveals the presence of extensions and rearrangements in C. elegans subunits associated with maintaining the dimer interface. We speculate that increasing dimer angles could provide an advantage for species that inhabit variable-oxygen environments by forming flatter more energetically efficient cristae.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10903453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139073335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Up-regulation of SLC7A11/xCT creates a vulnerability to selenocystine-induced cytotoxicity SLC7A11/xCT 的上调使人容易受到硒胱氨酸诱导的细胞毒性的影响

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2023-12-20 DOI: 10.1042/bcj20230317

Tan, Shawn Lu Wen, Tan, Hui Min, Israeli, Erez, Fatihah, Indah, Ramachandran, Vignesh, Ali, Shamsia Bte, Goh, Shane Jun An, Wee, Jillian, Tan, Alicia Qian Ler, Tam, Wai Leong, Han, Weiping

引用次数: 0