Journal of Biological Chemistry最新文献_第10页

"Death, taxes, and rhomboids: Understanding the ubiquitous roles of the rhomboid protein super-family". “死亡、税收和菱形：了解菱形蛋白超级家族的普遍作用”。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-12 DOI: 10.1016/j.jbc.2025.110699

Henry Sawczyc,Spyridon Kosteletos,Adam Lange

{"title":"\"Death, taxes, and rhomboids: Understanding the ubiquitous roles of the rhomboid protein super-family\".","authors":"Henry Sawczyc,Spyridon Kosteletos,Adam Lange","doi":"10.1016/j.jbc.2025.110699","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110699","url":null,"abstract":"The rhomboid super-family is the largest family of membrane proteins, containing over 122,000 members (both active and inactive proteases) across nearly all domains of life. The high number of members, as well as the conserved roles undertaken by members indicates an ancient origin and nature of function. However, the high structural similarity and multiple active homologs per species or cell has made specific functional characterisation difficult. Where function is known, members appear to be not imminently necessary for life, but organisational or housekeeping in nature. Historically, active protease members have been the focus of research, due to the ease of biochemical characterisation through monitoring proteolytic cleavage. The active members appear to possess conserved and specific recognition motifs for substrates, although no consensus sequence for substrates exist. Instead substrate access and recognition appear to occur through recognition by dynamics. In recent years, bioinformatic work has shifted focus towards catalytically inactive members, and the functional characterisation of these numerous but oft forgotten 'dead' proteases. These inactive proteases are now known to play key roles in the recognition and retrotranslocation of poor-quality membrane proteins. Recent work on the rhomboid-fold's unique ability to thin the lipid bilayer has enhanced mechanistic knowledge of both inactive and active protease function. Due to the ubiquitous presence of rhomboid members and their implications in a wide range of disease states, they are high priority pharmaceutical targets, however development of specific inhibitors has been hampered by the tight conservation of both the active site and the common rhomboid fold.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"17 1","pages":"110699"},"PeriodicalIF":4.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059232","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

From Pores to Rupture: Structural Basis and Regulation of Lytic Cell Death by Gasdermins and NINJ1. 从气孔到破裂：气胚乳和NINJ1裂解细胞死亡的结构基础和调控。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-12 DOI: 10.1016/j.jbc.2025.110698

Chengliang Wang,Brooke Dreyer,Evelyn Teran,Jianbin Ruan

{"title":"From Pores to Rupture: Structural Basis and Regulation of Lytic Cell Death by Gasdermins and NINJ1.","authors":"Chengliang Wang,Brooke Dreyer,Evelyn Teran,Jianbin Ruan","doi":"10.1016/j.jbc.2025.110698","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110698","url":null,"abstract":"Gasdermins (GSDMs) are a family of pore-forming proteins that execute lytic cell death by forming large β-barrel pores in cellular membranes. While traditionally regarded as the terminal effectors of pyroptosis, recent advances have revealed that GSDM pores alone are insufficient to cause full plasma membrane rupture, prompting the identification of NINJ1 as a critical executor of terminal cell lysis. This review provides an in-depth overview of the structural basis of GSDM pore formation and the regulatory mechanisms that govern their activity, including diverse post-translational modifications such as ubiquitination, palmitoylation, and PARylation. We also expand our discussion to the non-canonical activation strategies observed in bacterial, fungal, and ancient eukaryotic GSDM homologs. We further explore the molecular mechanisms for NINJ1 activation, highlighting its global role in mediating plasma membrane rupture downstream of multiple lytic cell death pathways. Finally, we discuss the pathological implications of dysregulated NINJ1 activity in related diseases, emphasizing its therapeutic potential as a universal modulator of terminal cell rupture.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"53 1","pages":"110698"},"PeriodicalIF":4.8,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145059229","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 Bias in Vitamin A Metabolism: Why α-Retinoids Miss the Eye. 维生素A代谢的结构偏差：为什么α-类维生素A错过了眼睛。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-11 DOI: 10.1016/j.jbc.2025.110713

Sepalika Bandara,Aicha Saadane,Pranesh Ravichandran,Srinivasagan Ramkumar,Johannes von Lintig

{"title":"Structural Bias in Vitamin A Metabolism: Why α-Retinoids Miss the Eye.","authors":"Sepalika Bandara,Aicha Saadane,Pranesh Ravichandran,Srinivasagan Ramkumar,Johannes von Lintig","doi":"10.1016/j.jbc.2025.110713","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110713","url":null,"abstract":"Provitamin A carotenoids are metabolized to retinoids, critical for vision and transcriptional regulation, through oxidative cleavage by carotenoid oxygenases. β-Carotene, a symmetric carotenoid, undergoes central cleavage by β-carotene oxygenase 1 (BCO1), generating two molecules of retinaldehyde. In contrast, the metabolism of asymmetric carotenoids, such as α-carotene (β,ε-carotene) and β-cryptoxanthin (β,β-carotene-3-ol), produces noncanonical apocarotenoid derivatives in addition to retinaldehyde. Here, we dissect the enzymatic pathways and transport mechanisms governing these metabolic fates in mice. We demonstrate that α-carotene is cleaved exclusively by BCO1 to yield retinaldehyde and α-retinaldehyde, bypassing mitochondrial processing. β-Cryptoxanthin, however, undergoes an initial eccentric cleavage by mitochondrial BCO2, followed by cytosolic BCO1-mediated central cleavage, producing only retinaldehyde. This divergence arises from differential subcellular trafficking: β-cryptoxanthin is transported to mitochondria via Aster-B, while α-carotene is excluded. Downstream, α-retinol is esterified by lecithin:retinol acyltransferase (LRAT), trafficked in chylomicrons, and stored as α-retinyl esters in the liver under ISX-mediated transcriptional control. Notably, α-retinol is not mobilized into circulation via retinol binding protein 4 (RBP4), and, genetic ablation of its receptor, STRA6 does not alter α-retinyl ester storage in lung tissue. Intriguingly, α-retinyl esters accumulate in the eyes of STRA6-deficient mice yet fail to participate in the visual cycle due to exclusion from RPE65-mediated isomerization. These findings establish α-retinoids as metabolic tracers of BCO1 activity and chylomicron-mediated vitamin A delivery and reveal mechanistic safeguards that prevent incorporation of noncanonical retinoids into the visual cycle.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"24 1","pages":"110713"},"PeriodicalIF":4.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056667","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 trypanosome vault particle is composed of multiple major vault protein paralogs and harbors vault RNA. 锥虫的穹窿颗粒由多个主要的穹窿蛋白类似物组成，并含有穹窿RNA。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-11 DOI: 10.1016/j.jbc.2025.110706

Anna Zavrelova,Siqi Shen,Farnaz Zahedifard,Emmanuel Ayodeji Agbebi,Silke Braune,Susanne Kramer,Martin Zoltner

{"title":"The trypanosome vault particle is composed of multiple major vault protein paralogs and harbors vault RNA.","authors":"Anna Zavrelova,Siqi Shen,Farnaz Zahedifard,Emmanuel Ayodeji Agbebi,Silke Braune,Susanne Kramer,Martin Zoltner","doi":"10.1016/j.jbc.2025.110706","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110706","url":null,"abstract":"Many, but not all Eukaryotes have protein-enclosed compartments called vaults. Vaults are composed of multiple copies of the major vault protein, symmetrically assembled into a basket-like shell. A human cell contains approximately 100,000 vault particles, the vast majority localized to the cytosol but also observed in the nucleus and at the nuclear pore complex. Whilst there is intriguing structural information of the vault shell, the function of vaults remains largely elusive, apart from a potential contribution to mRNA maturation. We set out to explore the vault interactome in the early branching eukaryote Trypanosoma brucei employing a combination of affinity capture and TurboID proximity labelling. T. brucei encodes three major vault protein (MVP) paralogs which exhibit a considerable degree of divergence. Unexpectedly, affinity capture proteomics with one MVP as a bait precipitated the other two paralogs, detected with similar intensities, indicating the possibility that all three are incorporated into the same particle. Dual color fluorescence microscopy of MVP pairs fused with different GFP-variants confirmed that all three paralogs are incorporated into a single vault shell. Our combined interactome data, including immune-isolations with varying stringencies, suggest a vault particle core composition of three MVPs homologs and the telomerase associated protein 1 (TEP1), which has been described as vault component in various organisms. Further, we demonstrate association of vtRNA with the particle and suggest a cohort of potential transient vault interactors, dominated by RNA binding proteins and splicing factors, which were found enriched in both orthogonal interactome approaches.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"53 1","pages":"110706"},"PeriodicalIF":4.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056674","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

BATF2-Mediated Control of Astrocyte Proliferation. batf2介导的星形胶质细胞增殖控制。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-11 DOI: 10.1016/j.jbc.2025.110710

Rachel A Tinkey, Benjamin J Frostino, Maria L Habean, Jessica L Williams

{"title":"BATF2-Mediated Control of Astrocyte Proliferation.","authors":"Rachel A Tinkey, Benjamin J Frostino, Maria L Habean, Jessica L Williams","doi":"10.1016/j.jbc.2025.110710","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110710","url":null,"abstract":"<p><p>Astrocyte proliferation in the central nervous system (CNS) is tightly controlled and is driven by the coordinated expression of regulatory proteins including cyclins and cyclin-dependent kinases (CDKs) that dictate cell cycle progression. While most of the post-natal proliferation in the CNS occurs in well-defined stem cell niches, proliferation of differentiated glial cells can also be observed to maintain local populations during homeostasis and in response to inflammation. However, the transcriptional programs that regulate homeostatic proliferation of terminally differentiated astrocytes is not fully understood. Here, we identify a novel basic leucine zipper ATF-like transcription factor (BATF)2 as a prominent regulator of cell cycle genes in astrocytes. Specifically, loss of BATF2 resulted in increased expression of proliferation proteins including Ki67 and phospho-histone H3. Further, chromatin immunoprecipitation sequencing revealed that BATF2 binds to regulatory regions of several cell cycle-related genes that encode cyclin-dependent kinases regulatory subunit (CKS)1B, CDK2, and cyclin D1. Concomitantly, we found that deletion of BATF2 increased transcription of these target genes. In addition, we examined the relationship of BATF2 and cyclin D1 in patient-derived glioblastoma samples and found that elevated levels of BATF2 had a corresponding decrease in cyclin D1. Collectively, our study demonstrates that BATF2 participates in the control of astrocytic cell cycle gene expression and further highlights BATF2 as a suppressor of uncontrolled proliferation.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110710"},"PeriodicalIF":4.0,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058310","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

Important amino acid residues in the chloride pump halorhodopsin that accelerate ion transport despite no direct interaction with the substrate. 尽管与底物没有直接的相互作用，但氯泵盐紫红质中加速离子运输的重要氨基酸残基。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-11 DOI: 10.1016/j.jbc.2025.110703

Yubo Zhai,Anna Shimosaka,Takashi Tsukamoto,Takashi Kikukawa

{"title":"Important amino acid residues in the chloride pump halorhodopsin that accelerate ion transport despite no direct interaction with the substrate.","authors":"Yubo Zhai,Anna Shimosaka,Takashi Tsukamoto,Takashi Kikukawa","doi":"10.1016/j.jbc.2025.110703","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110703","url":null,"abstract":"Ion-pump rhodopsins are widely distributed photoactive membrane proteins found in microorganisms. Their cytoplasmic (CP) regions are predominantly hydrophobic, inherently restricting substrate ion permeation. However, these rhodopsins can rapidly transport substrate ions via photo-induced conformational changes. The well-characterized H+-pumping rhodopsins employ dissociable residues such as Asp, Glu, or Lys to mediate rapid H+ relay reactions along a transiently hydrated CP pathway. In contrast, the corresponding mechanisms in other ion pumps remain poorly understood. Here, we investigated the key factors contributing to ion transport by halorhodopsin (HR), a Cl- pump from the archaeon Natronomonas pharaonis (NpHR). Upon photoactivation, NpHR creates a hydrated Cl- transport pathway in its CP region, which is surrounded by bulky hydrophobic residues that do not directly interact with Cl-. However, mutations in specific hydrophobic residues significantly slow Cl- transport. Notably, Phe211 and Leu214, located near the pathway exit, play critical roles. Mutations in these residues likely disrupt the proper positioning of the Lys215 sidechain, which inadvertently binds Cl- from the surrounding solution and positions it in a way that obstructs Cl- transport. As a result, ion passage is hindered, leading to the accumulation of long-lived intermediates. These findings suggest that the hydrophobic residues surrounding the pathway are not merely structural components. Instead, they are critical for enabling specific conformational changes that facilitate the formation of a hydrated channel, allowing efficient Cl- conduction without obstruction.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"77 1","pages":"110703"},"PeriodicalIF":4.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056658","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 effects of naturally occurring mutations on functionality of oxylipin metabolizing dehydrogenase reductase 9. 自然突变对氧化脂代谢脱氢酶还原酶功能的影响。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-11 DOI: 10.1016/j.jbc.2025.110704

Samuel E Wirth,Svetlana Pakhomova,Olga V Belyaeva,William E Boeglin,Alan R Brash,Marcia E Newcomer,Natalia Y Kedishvili,Kirill M Popov

{"title":"The effects of naturally occurring mutations on functionality of oxylipin metabolizing dehydrogenase reductase 9.","authors":"Samuel E Wirth,Svetlana Pakhomova,Olga V Belyaeva,William E Boeglin,Alan R Brash,Marcia E Newcomer,Natalia Y Kedishvili,Kirill M Popov","doi":"10.1016/j.jbc.2025.110704","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110704","url":null,"abstract":"Recent evidence indicates dehydrogenase reductase 9 (DHRS9) can oxidize and alter the biological activity of a diverse group of oxylipin substrates, underscoring the importance of DHRS9 in the regulation of a variety of biological processes such as inflammation, cell proliferation, and tissue repair. Importantly, mutations in DHRS9 gene resulting in amino acid substitutions S202L and D286H have been linked to an early onset case of epilepsy; whether these mutations affect the function of DHRS9 has not been investigated. The results of this study demonstrate that both mutations cause significant loss of DHRS9 functionality. However, in the case of S202L variant, the loss of catalytic activity likely stems from the impaired protein folding and/or protein stability. On the other hand, D286H DHRS9 mutant protein is relatively more stable than S202L variant, but its Km value for NAD+ (2.85 mM) is nearly 12-fold higher than that of the wild type enzyme. The three-dimensional structure of DHRS9 solved in this study provides insights into the functions of S202 and D286 residues. In addition, it reveals a strikingly large substrate binding cavity, consistent with the fact that the enzyme can process oxygenated hydrocarbons with abundant rotational freedom and of differing lengths (18-22 C). Considering that expression levels of DHRS9 in human tissues are highly sensitive to inflammatory conditions, and the existence of naturally occurring mutations in DHRS9, the structural and functional characterization of DHRS9 reported in this study is critical for a better understanding of the role of DHRS9 in inflammatory processes.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"16 1","pages":"110704"},"PeriodicalIF":4.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056663","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

Binding of a [2Fe-2S] cluster drives dimerization of ferric uptake regulator (Fur) in Escherichia coli. [2Fe-2S]簇的结合驱动了大肠杆菌中铁摄取调节剂（Fur）的二聚化。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-11 DOI: 10.1016/j.jbc.2025.110702

Fatemeh Najafi,Aidan G Purcell,Finbar H Homes,Huangen Ding

{"title":"Binding of a [2Fe-2S] cluster drives dimerization of ferric uptake regulator (Fur) in Escherichia coli.","authors":"Fatemeh Najafi,Aidan G Purcell,Finbar H Homes,Huangen Ding","doi":"10.1016/j.jbc.2025.110702","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110702","url":null,"abstract":"The ferric uptake regulator (Fur) is a global transcription factor that reversibly binds a [2Fe-2S] cluster via the cysteine residues (site 3) in response to elevation of intracellular free iron content in Escherichia coli. Here we report that when E. coli Fur is expressed in E. coli cells grown in M9 medium supplemented with iron or zinc, purified Fur binds a [2Fe-2S] cluster or Zn(II), respectively. While apo-form Fur is a monomer and has no DNA binding activity, both the [2Fe-2S] cluster-bound Fur and the Zn(II)-bound Fur are homodimers and have a similar binding activity for the DNA sequence known as the Fur-box. The ICP-MS analyses show that the purified [2Fe-2S] cluster-bound Fur homodimer binds only one [2Fe-2S] cluster per monomer and no other transition cations, and that the Zn(II)-bound Fur homodimer binds only one Zn(II) per monomer. The site-directed mutagenesis studies reveal that Fur binds the [2Fe-2S] cluster or Zn(II) at the same binding site (site 3) via the cysteine residues. While deletion of the iron-sulfur cluster assembly scaffold protein IscU prevents the [2Fe-2S] cluster assembly in Fur, deletion of IscU has no effect on the Zn(II) binding in Fur. Furthermore, the addition of Zn(II) effectively inhibits the [2Fe-2S] cluster binding in Fur in E. coli cells grown in M9 medium. The results suggest that E. coli Fur dimerizes upon the binding of a [2Fe-2S] cluster at site 3, and that Zn(II) competes with the [2Fe-2S] cluster binding in Fur and disrupts the regulation of intracellular iron homeostasis.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"47 1","pages":"110702"},"PeriodicalIF":4.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056661","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 anti-apoptotic BCL2 overcomes adaptive resistance to co-targeting of the protein kinase FAK and MEK in GNAQ-driven uveal melanoma. 在gnaq驱动的葡萄膜黑色素瘤中，抑制抗凋亡的BCL2克服了蛋白激酶FAK和MEK共同靶向的适应性抵抗。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-11 DOI: 10.1016/j.jbc.2025.110712

Simone Lubrano,Rodolfo Daniel Cervantes-Villagrana,Nadia Arang,Adam Officer,Sendi Rafael Adame-Garcia,Gabriela Cuesta-Margolles,Andrew E Aplin,J Silvio Gutkind

{"title":"Inhibition of anti-apoptotic BCL2 overcomes adaptive resistance to co-targeting of the protein kinase FAK and MEK in GNAQ-driven uveal melanoma.","authors":"Simone Lubrano,Rodolfo Daniel Cervantes-Villagrana,Nadia Arang,Adam Officer,Sendi Rafael Adame-Garcia,Gabriela Cuesta-Margolles,Andrew E Aplin,J Silvio Gutkind","doi":"10.1016/j.jbc.2025.110712","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110712","url":null,"abstract":"Uveal melanoma (UVM) is the most common eye cancer in adults, with 50% of patients developing overt metastasis that often proves fatal. The majority of UVM harbor mutations in GNAQ or GNA11, encoding constitutively active Gαq proteins. Combined inhibition of MEK and FAK downstream of Gαq has shown promising effects in UVM cells by inducing apoptotic cell death, but resistance to this strategy can occur in the clinic. Here, we aimed to identify new targets to overcome resistance to MEK + FAK inhibition (FAKi+MEKi). Reverse-phase protein array (RPPA) analysis in UVM cells treated with FAKi+MEKi showed increased levels of pro-apoptotic proteins such as PUMA and BIM, which promoted cell death. However, we observed an adaptive increase in anti-apoptotic proteins, including BCL2, upon FAK+MEK blockade. We generated UVM cells resistant to FAKi+MEKi by prolonged exposure. Whole-exome sequencing did not reveal relevant acquired mutations; instead, resistant cells exhibit increased BCL2 levels. Moreover, expression of a stable BCL2 mutant confers resistance to both FAKi+MEKi and FAKi+\"RAF-MEK clamp\" (avutometinib) treatment. Of direct translational relevance, we found that an approved BCL2 inhibitor (venetoclax) displays synergistic efficacy with FAK+MEK blockade and overcomes acquired resistance, including when combined with darovasertib, a dual PKC/PKN inhibitor limiting MEK and FAK signaling that is under clinical evaluation. Our findings suggest that resistance to FAKi+MEKi in UVM cells can be driven by an adaptive upregulation of the anti-apoptotic protein BCL2, and that, in turn, BCL2 inhibitors represent a promising precision-targeted strategy to overcome FAKi+MEKi treatment resistance and improve therapeutic outcomes.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"1 1","pages":"110712"},"PeriodicalIF":4.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056668","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

Filamentous structure of the CotVW complex, the crust proteins of the Bacillus subtilis endospore. 枯草芽孢杆菌内孢子外壳蛋白CotVW复合体的丝状结构。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-11 DOI: 10.1016/j.jbc.2025.110714

Eunbyul Jo,Doyeon Kim,Yeongjin Baek,Migak Park,Hyojeong Lee,Nam-Chul Ha

{"title":"Filamentous structure of the CotVW complex, the crust proteins of the Bacillus subtilis endospore.","authors":"Eunbyul Jo,Doyeon Kim,Yeongjin Baek,Migak Park,Hyojeong Lee,Nam-Chul Ha","doi":"10.1016/j.jbc.2025.110714","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110714","url":null,"abstract":"The endospores of Bacillus subtilis are encased in a multilayered protective structure comprising core, cortex, inner and outer coats, and an outermost crust. Among the proteins required for crust formation, CotV and CotW are unique to B. subtilis and are hypothesized to be instrumental in maintaining spore surface integrity. However, their structural organization and functional mechanisms remain unclear. This study determined the cryogenic electron microscopy (cryo-EM) structure of the CotVW complex and revealed its filamentous helical architecture. Structural analysis showed that CotVW possesses a negatively charged surface that enables pH-dependent binding interactions. Specifically, at pH 6.0, CotVW engages in electrostatic interactions with histidine and positively charged residues, suggesting a potential regulatory mechanism influenced by the environmental pH. Our results elucidate the molecular basis of CotVW function in B. subtilis spore crust formation, highlighting its role in spore surface organization. This study advances our understanding of the spore coat architecture and may inform future research on bacterial spore resilience and structural adaptation.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"170 1","pages":"110714"},"PeriodicalIF":4.8,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145056669","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