Journal of Biological Chemistry最新文献_第6页

SLC39A5 promotes the malignant progression of gastric cancer by activating BATF phosphorylation. SLC39A5通过激活BATF磷酸化促进胃癌恶性进展。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-22 DOI: 10.1016/j.jbc.2025.110754

Xinyu Wang,Tao Li,Mingxi Xia,Leichao Sun,Xudong Wang

{"title":"SLC39A5 promotes the malignant progression of gastric cancer by activating BATF phosphorylation.","authors":"Xinyu Wang,Tao Li,Mingxi Xia,Leichao Sun,Xudong Wang","doi":"10.1016/j.jbc.2025.110754","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110754","url":null,"abstract":"Despite advances in diagnostic and therapeutic methods for gastric cancer (GC), early detection continues to be a significant challenge, resulting in late-stage diagnoses and poor survival outcomes. Studies have shown that solute carrier family 39 member 5 (SLC39A5) is upregulated in GC and may serve as a potential prognostic biomarker. However, the exact role of SLC39A5 and its underlying mechanisms remains unclear. To evaluate cell proliferation, migration, and invasion, a variety of assays, including Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, scratch, and Transwell assays, were conducted. The molecular interactions among genes were investigated through co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), and dual luciferase reporter assays. An in vivo GC mouse model was established to substantiate our in vitro findings. Knockdown of SLC39A5 inhibited GC cell proliferation, migration, and invasion. Furthermore, SLC39A5 increased Moloney murine leukemia virus 1 (PIM1) kinase activity by enhancing zinc influx, which in turn triggered basic leucine zipper ATF-like transcription factor (BATF) phosphorylation and stabilized BATF protein. BATF overexpression reversed the inhibitory effect of SLC39A5 depletion on the behavior of GC cells and tumor growth. Moreover, we found that BATF, combined with the jun proto-oncogene, AP-1 transcription factor subunit (JUN), led to the suppression of huntingtin interacting protein 1-related (HIP1R) expression and the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway. In conclusion, SLC39A5 promotes the progression of GC via the BATF/HIP1R axis, which suggests that SLC39A5 acts as a therapeutic or diagnostic target for GC.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"41 1","pages":"110754"},"PeriodicalIF":4.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133998","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

SAG1.3-derived Frizzled-targeting small molecule compounds. sag1.3衍生的frizzed靶向小分子化合物。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-22 DOI: 10.1016/j.jbc.2025.110751

Lukas Grätz, Ainoleena Turku, Pawel Kozielewicz, Carl-Fredrik Bowin, Magdalena M Scharf, Jan H Voss, Julia Kinsolving, Rawan Shekhani, Nuria Oliva-Vilarnau, Tobias Koolmeister, Marlies Körber, Volker M Lauschke, Stefan Löber, Peter Gmeiner, Gunnar Schulte

{"title":"SAG1.3-derived Frizzled-targeting small molecule compounds.","authors":"Lukas Grätz, Ainoleena Turku, Pawel Kozielewicz, Carl-Fredrik Bowin, Magdalena M Scharf, Jan H Voss, Julia Kinsolving, Rawan Shekhani, Nuria Oliva-Vilarnau, Tobias Koolmeister, Marlies Körber, Volker M Lauschke, Stefan Löber, Peter Gmeiner, Gunnar Schulte","doi":"10.1016/j.jbc.2025.110751","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110751","url":null,"abstract":"Exaggerated Wingless/Int1 (WNT)/Frizzled (FZD) signaling contributes to pathologies including fibrosis and different forms of cancers. Thus, targeting FZDs as WNT receptors for therapeutic purposes constitutes a promising intervention if the imminent risk of unwanted side effects caused by the involvement of WNT/FZD signaling in stem cell regulation and tissue homeostasis can be controlled. Here, we derivatize SAG1.3, which acts through FZD6 as a partial agonist. Screening of SAG1.3 derivatives identified compound 11 that competed with BODIPY-cyclopamine binding at different FZDs and inhibited WNT-induced FZD dynamics and β-catenin signaling in HEK293 cells. Furthermore, compound 11 blocked WNT-3A-induced Lgr5 gene expression in human primary hepatocyte spheroids and reduced the viability of RNF43-mutated but not RNF43-wildtype pancreatic cancer cells. Based on our data, we suggest that compound 11 acts on FZDs to limit WNT- and WNT-surrogate-induced receptor dynamics providing a valid proof-of-concept for targeting FZDs with small molecule compounds.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110751"},"PeriodicalIF":4.0,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137621","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

UBE2O, a host ubiquitin-conjugating enzyme, is a key regulator of Hepatitis B virus maturation and egress. 宿主泛素结合酶ube20是乙型肝炎病毒成熟和输出的关键调控因子。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-22 DOI: 10.1016/j.jbc.2025.110750

Barbora Lubyova,Eva Tikalova,Vaclav Janovec,Boris Ryabchenko,Kristyna Krulova,Vaclav Kropacek,Sandra Huerfano,Ivan Hirsch,Jan Weber

{"title":"UBE2O, a host ubiquitin-conjugating enzyme, is a key regulator of Hepatitis B virus maturation and egress.","authors":"Barbora Lubyova,Eva Tikalova,Vaclav Janovec,Boris Ryabchenko,Kristyna Krulova,Vaclav Kropacek,Sandra Huerfano,Ivan Hirsch,Jan Weber","doi":"10.1016/j.jbc.2025.110750","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110750","url":null,"abstract":"A critical step in Hepatitis B virus (HBV) maturation and egress is the ubiquitination of the capsid/core protein (HBc), which enables its recognition by the endosomal sorting complex required for transport (ESCRT) machinery and recruitment to multivesicular bodies (MVBs). This study investigates the role of UBE2O, an atypical E2 ubiquitin-conjugating enzyme with intrinsic E3 ligase activity, in nucleocapsid assembly and virion egress. Loss of UBE2O in HBV-infected primary human hepatocytes (PHH) and HepG2-NTCP cells led to a reduction in viral replication, as evidenced by decreased levels of intracellular HBV DNA, pgRNA, capsids, and extracellular HBeAg. Additionally, UBE2O depletion disrupted intracellular nucleocapsid assembly and impaired the secretion of enveloped virions, but the release of naked nucleocapsids remained unaffected. In contrast, UBE2O overexpression enhanced the secretion of mature virions, whereas the expression of its enzymatically inactive mutant inhibited this process. Additionally, UBE2O mediated the monoubiquitination of hypophosphorylated cytoplasmic HBc and capsids. Subcellular localization experiments using confocal microscopy and proximity ligation assays (PLA) demonstrated that UBE2O colocalizes with capsids and ubiquitinated cargo in CD63-positive MVB compartments, indicating its involvement in the endosomal secretory pathway. Collectively, this study identifies UBE2O and its catalytic activity as key regulators of the HBV virion secretion pathway, highlighting its potential as a therapeutic target for HBV treatment.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"13 1","pages":"110750"},"PeriodicalIF":4.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133995","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

Type II Polyketide Synthases: impact on human health, current knowledge, and future directions. II型聚酮合酶：对人类健康的影响，目前的知识和未来的方向。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-22 DOI: 10.1016/j.jbc.2025.110749

Jacob T Wolff,Shiou-Chuan Tsai

{"title":"Type II Polyketide Synthases: impact on human health, current knowledge, and future directions.","authors":"Jacob T Wolff,Shiou-Chuan Tsai","doi":"10.1016/j.jbc.2025.110749","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110749","url":null,"abstract":"Natural products have a long history of use in traditional and modern medicine due to their inherent bioactivity. Some medicinal activities include antibiotic, antifungal, anticancer, antiviral, antihypercholestrolemic, and immunosuppressant. One of the largest classes of bioactive natural products are polyketides, produced by polyketide synthases (PKS). PKS are closely related to fatty acid synthases (FAS), sharing a core biosynthetic logic that iteratively builds larger molecules from simple precursors. However, PKS produce compounds with incredible structural diversity and function through the accretion of small chemical alterations not available to FAS at each point during synthesis. Polyketide biosynthesis can be grouped into initiation, extension, reduction, aromatization and cyclization, and tailoring steps. Changes at each step have the potential to produce many variations in structure motivating prodigious research efforts to understand and engineer new PKS that produce novel medicinal compounds. Despite success creating chimeric PKS that produced new compounds, yield and fidelity were decreased, and these successes have made clear that understanding protein-protein interactions is critical for improved engineering outcomes. In this review we lay out of the importance of natural products assembled by type II PKSs in human health, and how these molecules are assembled, and conclude by summarizing the challenges currently facing the field.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"11 1","pages":"110749"},"PeriodicalIF":4.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133996","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

G-Quadruplex Specific Action of Chloroquine based Immunomodulator Drugs to Inhibit the Cancer Progression. 基于氯喹的免疫调节药物抑制肿瘤进展的g -四重体特异性作用。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-22 DOI: 10.1016/j.jbc.2025.110753

Sunipa Sarkar,Akash Chatterjee,Subhojit Paul,Asim Bisoi,Prosenjit Sen,Prashant Chandra Singh

{"title":"G-Quadruplex Specific Action of Chloroquine based Immunomodulator Drugs to Inhibit the Cancer Progression.","authors":"Sunipa Sarkar,Akash Chatterjee,Subhojit Paul,Asim Bisoi,Prosenjit Sen,Prashant Chandra Singh","doi":"10.1016/j.jbc.2025.110753","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110753","url":null,"abstract":"Immunomodulatory drugs, particularly hydroxychloroquine (HCQ) and chloroquine (CQ) are in the preclinical investigation for cancer therapy, along with their extensive application in autoimmune and parasitic diseases. A hallmark of cancer cells is the elevated expression of oncogenes that drive tumor progression, often regulated by G-quadruplex (G4) DNA structures located within their upstream promoter regions. This study elucidates that HCQ stabilizes the cellular G4 landscape most efficiently compared to other quinoline-based immunomodulatory drugs within oncogenic DNA, particularly the c-myc oncogene, a pivotal regulator of cancer progression. The drug-induced stabilization of c-myc G4 correlates with significant suppression of its transcriptional activity, culminating in a reduction of invasion and migration of TNBC cells. Mechanistically, the strong electrostatic interaction between the G4 phosphate backbone and the drug's charged side chain, anchors its quinoline group to enhance stacking with loop and quartet regions, stabilizing the G4. The in vivo investigation unveils the HCQ's capacity to potentiate the efficacy of conventional chemotherapeutic agents, representing it as a plausible candidate for adjunctive therapy. This study depicts an unconventional anticancer mechanism of immunomodulator drugs, wherein it exerts preferential transcriptional repression of the c-myc oncogene through G4-dependent stabilization, unveiling a novel strategy in oncological intervention.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"23 1","pages":"110753"},"PeriodicalIF":4.8,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145133997","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

New Biochemical Approaches for Treatment of Glioblastoma. 治疗胶质母细胞瘤的新生化方法。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-20 DOI: 10.1016/j.jbc.2025.110748

Laura A Lindsey-Boltz,Aziz Sancar

引用次数: 0

Molecular basis of IFN-γ-induced STAT3 phosphorylation stimulated by Sendai virus C protein. 仙台病毒C蛋白诱导IFN-γ诱导STAT3磷酸化的分子基础

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-18 DOI: 10.1016/j.jbc.2025.110744

Kosuke Oda,Yuta Hatori,Atsuji Kodama,Susumu Uchiyama,Takashi Oda,Yasuyuki Matoba,Ami Nakano,Kanako Ninomiya,Seira Yoshidomi,Takemasa Sakaguchi

{"title":"Molecular basis of IFN-γ-induced STAT3 phosphorylation stimulated by Sendai virus C protein.","authors":"Kosuke Oda,Yuta Hatori,Atsuji Kodama,Susumu Uchiyama,Takashi Oda,Yasuyuki Matoba,Ami Nakano,Kanako Ninomiya,Seira Yoshidomi,Takemasa Sakaguchi","doi":"10.1016/j.jbc.2025.110744","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110744","url":null,"abstract":"Sendai virus (SeV), belonging to the Respirovirus genus in the Paramyxoviridae family, possesses C protein to escape from host innate immunity by inhibiting the IFN-α/β-induced STAT1:STAT2 pathway and the IFN-γ-induced STAT1 pathway via binding to the N-terminal domain of STAT1 (STAT1ND). In this study, a yeast two-hybrid analysis revealed that C protein also binds directly to the N-terminal domain of STAT3 (STAT3ND). The C-terminal region of C protein (named Y3) was sufficient for binding to STAT3ND, similar to STAT1ND binding. However, the affinity of Y3 for STAT3ND was significantly weaker than that for STAT1ND. Transfection experiments using 293T cells demonstrated that the introduction of C protein significantly stimulated the IFN-γ-induced phosphorylation of STAT3. Considering the results of stoichiometric and confocal analyses together, C protein likely plays a role in stabilizing the dimeric structure formed by STAT3ND, stimulating the recruitment of dimeric STAT3 to the plasma membrane. Reporter assay demonstrated the persistent activation of the STAT3 pathway in the presence of C protein after IFN-γ stimulation. The STAT1 homodimer, bound to two molecules of C protein, cannot take an active form to promote the transcription of target genes. In contrast, STAT3 can take an active form even in the presence of C protein, probably because the complex formed between them is fragile.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"53 1","pages":"110744"},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093563","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

Rules of engagement: determinants of chemokine receptor activation and selectivity by CCL27 and CCL28. 交战规则：CCL27和CCL28的趋化因子受体激活和选择性的决定因素。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-18 DOI: 10.1016/j.jbc.2025.110736

Mian Huang, Aura F Celniker, Rezvan Chitsazi, Douglas P Dyer, Ariane L Jansma, Irina Kufareva, Catherina L Salanga, Tracy M Handel

{"title":"Rules of engagement: determinants of chemokine receptor activation and selectivity by CCL27 and CCL28.","authors":"Mian Huang, Aura F Celniker, Rezvan Chitsazi, Douglas P Dyer, Ariane L Jansma, Irina Kufareva, Catherina L Salanga, Tracy M Handel","doi":"10.1016/j.jbc.2025.110736","DOIUrl":"10.1016/j.jbc.2025.110736","url":null,"abstract":"The distinct functional roles of chemokines CCL27 and CCL28 in epithelial immunity of skin and mucosal tissues, respectively, are coordinated by their shared receptor, CCR10, and the CCL28-specific receptor, CCR3. To identify determinants of receptor activation, internalization and binding specificity, we conducted structure-function studies focused on the N-termini of these two chemokines. Deletion of two N-terminal residues of CCL27 resulted in a CCR10 antagonist, highlighting the critical roles of these residues in driving receptor pharmacology. Extension with a Phe produced a CCR10 superagonist by occupying a unique subpocket in the receptor. Swapping the CCL28 N-terminus onto the CCL27 globular domain (NT28-CCL27) also resulted in a superagonist of CCR10, but the opposite swap (NT27-CCL28) showed equivalent or reduced activity compared to WT CCL28, indicating that the CCL28 N-terminus is a stronger driver of CCR10 signaling. The effects of these mutations were rationalized by AlphaFold models of the CCR10 complexes. Modeling also revealed that the reduced size of the binding pocket, and more basic nature of the N-terminus and extracellular loops of CCR3 compared to CCR10, contribute to its specificity for CCL28 while CCR10 accommodates both ligands. The basic nature of CCL28 also contributes to its high affinity for glycosaminoglycans, and is likely important for its retention in mucosal tissues. These data illustrate how the modular nature of these chemokines enables their overlapping but non-redundant functions, and how this modularity can be exploited to produce engineered chemokines for probing or targeting CCR10 in disease.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"110736"},"PeriodicalIF":4.0,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102696","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

Putative receptors and signaling pathways responsible for the biological actions of epoxyeicosatrienoic acids. 环氧二碳三烯酸生物学作用的推定受体和信号通路。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-18 DOI: 10.1016/j.jbc.2025.110737

Matthew L Edin,Joan P Graves,Darryl C Zeldin

{"title":"Putative receptors and signaling pathways responsible for the biological actions of epoxyeicosatrienoic acids.","authors":"Matthew L Edin,Joan P Graves,Darryl C Zeldin","doi":"10.1016/j.jbc.2025.110737","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110737","url":null,"abstract":"Epoxy fatty acids (EpFAs), including arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), are endogenously produced bioactive signaling molecules with diverse physiological effects, including vasodilation, anti-inflammation, and cardioprotection. EETs are generated by a subset of cytochromes P450 and their biological activity is reduced by hydrolysis to dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolases. Inhibition of soluble epoxide hydrolase (sEH) has shown significant therapeutic promise in preclinical models of disease. Despite the profound physiological impact of EETs and the therapeutic potential of sEH inhibitors, the precise signaling mechanisms by which EETs elicit their biological effects remain unknown. Many have sought to identity a high-affinity, EET-activated, G-protein-coupled receptor (GPCR). This review synthesizes current knowledge regarding the evidence supporting the existence of one or more EET-GPCRs and weighs this evidence against alternative or complementary EET signaling pathways. The breadth of these studies highlights the complexities and challenges in fully elucidating the precise molecular mechanisms of EET actions.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"37 1","pages":"110737"},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093564","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

Intrinsically disordered cytoplasmic tail in netrin receptor DCC binds the large ribosomal subunit to inhibit translation. netrin受体DCC内在紊乱的细胞质尾部结合大核糖体亚基抑制翻译。

IF 4.8 2区生物学

Journal of Biological Chemistry Pub Date : 2025-09-18 DOI: 10.1016/j.jbc.2025.110741

Natasia Paukovich,Elizabeth A Spear,Andrea MacFadden,Nathan N Nowling,Morkos A Henen,Beat Vögeli,Megan E Filbin

{"title":"Intrinsically disordered cytoplasmic tail in netrin receptor DCC binds the large ribosomal subunit to inhibit translation.","authors":"Natasia Paukovich,Elizabeth A Spear,Andrea MacFadden,Nathan N Nowling,Morkos A Henen,Beat Vögeli,Megan E Filbin","doi":"10.1016/j.jbc.2025.110741","DOIUrl":"https://doi.org/10.1016/j.jbc.2025.110741","url":null,"abstract":"Transmembrane receptors in neurons act as transducers of extrinsic growth cues by regulating local protein synthesis of specific mRNAs to facilitate axon guidance. In the absence of cues, receptors tether and silence translation at the membrane, but little is known about this receptor-ribosome interaction. Here, we show the direct and specific interaction between the transmembrane receptor deleted in colorectal cancer, DCC, and the 60S subunit that leads to translation inhibition in the absence of DCC's growth cue, netrin-1. We combined translation assays, equilibrium binding, and NMR spectroscopic approaches and identified the plasma membrane-proximal portion of DCC's cytoplasmic tail, specifically residues 1123-1158, bind the 60S subunit. We show that this region is unstructured, providing evidence for how the subunit is tethered at the membrane. Pinpointing the electrostatic interaction between DCC and the 60S subunit protein eL5/uL18 that leads to translational silencing, we propose a two-part binding interaction that facilitates this function. Our findings reveal how DCC directly regulates local translation, shedding light on the role of transmembrane receptors in controlling protein synthesis during axon guidance.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"9 1","pages":"110741"},"PeriodicalIF":4.8,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093567","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