Journal of Biological Chemistry最新文献_第3页

Protein inhibitor of retinal membrane guanylyl cyclase rescues photoreceptors from degeneration induced by mutated guanylyl cyclase activating protein. 视网膜膜观酰基环化酶蛋白抑制剂对观酰基环化酶激活蛋白突变诱导的光感受器变性的修复作用。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-13 DOI: 10.1016/j.jbc.2026.113636

Lyuqi Tan, Igor V Peshenko, Elena V Olshevskaya, Alexander M Dizhoor

{"title":"Protein inhibitor of retinal membrane guanylyl cyclase rescues photoreceptors from degeneration induced by mutated guanylyl cyclase activating protein.","authors":"Lyuqi Tan, Igor V Peshenko, Elena V Olshevskaya, Alexander M Dizhoor","doi":"10.1016/j.jbc.2026.113636","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113636","url":null,"abstract":"Mutations in the GUCA1A gene coding for calcium-sensor protein GCAP1 cause congenital cone and cone-rod degenerations by disabling Ca2+-dependent reduction of cGMP synthesis in photoreceptors in the dark. Engineered protein inhibitor of guanylyl cyclase (PIGCY) effectively prevented in vitro stimulation of retinal membrane guanylyl cyclase (RetGC) by Y99C or E155G GCAP1, most commonly causing GUCA1A retinopathy. However, it was less effective against G86R and L176F GCAP1. PIGCY expressed in transgenic mouse rods (PIGCYTg) did not reverse the abnormal Ca2+-sensitivity of RetGC in mice harboring Y99C GCAP1 (Y99CTg) but reduced the overall cGMP production rate in dark-adapted PIGCYTgY99CTg retinas. PIGCY markedly slowed the progression of photoreceptor degeneration in Y99CTg mice: 84% of photoreceptor nuclei remained after 6 months in PIGCYTgY99CTg compared with only 30% in Y99CTg littermates. The histological layer of rod outer segments in the posterior retina was much better defined in aged PIGCYTgY99CTg mice than in Y99CTg littermates. Electroretinography (ERG) showed that PIGCY also dramatically rescued the light sensitivity of the dark-adapted Y99CTg rods. Whereas scotopic b-wave amplitude (rod ERG) diminished sixfold in Y99CTg compared with the wild type, it remained 80% of normal amplitude in PIGCYTgY99CTg littermates. ERG a-wave amplitude, generated by hyperpolarizing photoreceptors in response to a bright flash, was reduced more than tenfold in Y99CTg but only by 35% in PIGCYTgY99CTg. The results indicate that PIGCY can be considered for prospective gene therapy for some GCAP1 mutations causing dominant GUCA1A retinopathy.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113636"},"PeriodicalIF":4.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182034","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

RING E3 ligase TRIM8 is structurally selective for UBE2N-mediated ubiquitination. RING E3连接酶TRIM8对ube2n介导的泛素化具有结构选择性。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-13 DOI: 10.1016/j.jbc.2026.113642

Jane Dudley-Fraser, Diego Esposito, Katrin Rittinger

{"title":"RING E3 ligase TRIM8 is structurally selective for UBE2N-mediated ubiquitination.","authors":"Jane Dudley-Fraser, Diego Esposito, Katrin Rittinger","doi":"10.1016/j.jbc.2026.113642","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113642","url":null,"abstract":"RING domains catalyse ubiquitination by stabilising a closed conformation of E2-ubiquitin (Ub) conjugates, with TRIpartite Motif (TRIM) proteins representing the largest subfamily of RING-type E3 ligases. TRIM proteins are implicated in many physiological processes and diseases. For example, TRIM8 perturbation has been variously linked to neurodevelopmental defects and several cancer types, attributed to its ubiquitination of a myriad of putative substrates. However, the molecular mechanisms behind these modifications are not yet clear. Here we show that TRIM8 has preferential functionality with the E2 enzyme UBE2N to generate K63-linked poly-ubiquitin chains. By solving the crystal structure of TRIM8 RING bound to a UBE2N-Ub conjugate, we discover that its non-canonical asparagine 'linchpin' residue belies this selectivity by failing to form key contacts required to stabilise the closed conformation of other E2 enzymes. These findings not only open the door to exploring the impact of TRIM8-mediated K63 chain formation in health and disease, but also add to a growing appreciation of the specificities of RING domain catalytic activity.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113642"},"PeriodicalIF":4.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182088","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

LIF and let die: Generation, mechanistical and structural characterization of bispecific antibodies triggering leukemia inhibitory factor (LIF) receptor activation independent of the cytokine LIF. LIF和let die：独立于细胞因子LIF触发白血病抑制因子（LIF）受体激活的双特异性抗体的产生、机制和结构表征。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-09 DOI: 10.1016/j.jbc.2026.113634

Julia Harwardt, Silke Pudewell, Kristina Keil, Britta Lipinski, Laura Unmuth, Thi Hong Hue Tran, Enrico Guarnera, Desislava Elter, Lukas Pekar, Doreen M Floss, Jürgen Scheller, Andrew B Ward, Monica L Fernández-Quintero, Andreas Evers, Stefan Zielonka

{"title":"LIF and let die: Generation, mechanistical and structural characterization of bispecific antibodies triggering leukemia inhibitory factor (LIF) receptor activation independent of the cytokine LIF.","authors":"Julia Harwardt, Silke Pudewell, Kristina Keil, Britta Lipinski, Laura Unmuth, Thi Hong Hue Tran, Enrico Guarnera, Desislava Elter, Lukas Pekar, Doreen M Floss, Jürgen Scheller, Andrew B Ward, Monica L Fernández-Quintero, Andreas Evers, Stefan Zielonka","doi":"10.1016/j.jbc.2026.113634","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113634","url":null,"abstract":"Here, we report on the generation and characterization of single-domain antibody (sdAb)-derived bispecifics that mimic the function of LIF by triggering agonism on its heterodimeric receptor composed of the subunits LIF receptor (LIFR) and glycoprotein 130 (gp130). For this, LIFR-targeting sdAbs were identified by yeast surface display (YSD) after camelid immunization. Resulting 14 LIFR-specific paratopes were expressed in a bispecific antibody (bsAb) format all harboring the identical gp130-adressing sdAb. Profiling of bsAbs on Ba/F3 cells expressing human LIFR as well as gp130 revealed LIF-like functionality of one bsAb as characterized by the induction of cell proliferation. Cryo-EM structural analysis revealed that the bsAb targets a distinct LIFR epitope, indicating the formation of a receptor architecture that differs from previously reported LIF signaling complex structures. In addition, the identified sdAb-based bispecific LIF mimetic elicited STAT3 phosphorylation in HeLa as well as TF-1 cells naturally expressing the LIF receptor subunits. Moreover, agonism capabilities were further improved by antibody engineering. Taken together, we demonstrate that cytokine members of the IL-6 family can be mimicked by harnessing sdAbs as building blocks.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113634"},"PeriodicalIF":4.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148178","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 residues required for β-arrestin recruitment in the calcium-sensing receptor C-terminal tail may contribute to hypocalcemia. 钙敏感受体c端尾部β-阻滞蛋白募集所需残基的缺失可能导致低钙血症。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-09 DOI: 10.1016/j.jbc.2026.113633

Rachael A Wyatt, Hassan Massalha, Julia Drube, Carsten Hoffmann, Caroline M Gorvin

{"title":"Loss of residues required for β-arrestin recruitment in the calcium-sensing receptor C-terminal tail may contribute to hypocalcemia.","authors":"Rachael A Wyatt, Hassan Massalha, Julia Drube, Carsten Hoffmann, Caroline M Gorvin","doi":"10.1016/j.jbc.2026.113633","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113633","url":null,"abstract":"The calcium-sensing receptor (CaSR) is a family C G protein-coupled receptor (GPCR) with an important role in calcium homeostasis, activating mutations of which cause hypocalcemia. Despite the receptors clinical importance and evidence suggesting β-arrestin-1/2 can modulate CaSR signaling, the residues within CaSR required for β-arrestin recruitment and the role of β-arrestin in desensitization, trafficking and signaling are ill defined. We confirmed that β-arrestin-1 and β-arrestin-2 are recruited to CaSR upon receptor activation and that depletion of GPCR kinases impairs β-arrestin recruitment. Deletion of the distal CaSR C-terminal tail, which replicates several mutations identified in individuals with hypocalcemia, reduced β-arrestin-1/2 recruitment and enhanced receptor signaling. Examination of the receptor cytoplasmic region (intracellular loops and C-terminal tail) identified three regions of serine and threonine residues that resemble phosphorylation codes in other GPCRs. Mutation of each of these residues to alanine demonstrated one region between amino acids 1003-1011 is important for both β-arrestin-1 and β-arrestin-2 recruitment, while disruption of a region between residues 976-981 impaired β-arrestin-2 recruitment. Alanine mutagenesis of these residues also enhanced CaSR signaling and impaired receptor internalization suggesting an important role in receptor desensitization. Three rare-coding variants reported in disorders of calcium homeostasis were identified in these residues and two, T1006M and T1008P, were shown to reduce β-arrestin recruitment and CaSR internalization and enhance CaSR signaling. Thus, we have identified two regions within the CaSR C-terminal tail that are important for β-arrestin recruitment, receptor desensitization and internalization. Mutation of residues within these regions may represent another mechanism contributing to hypocalcemia.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113633"},"PeriodicalIF":4.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149861","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

Hepatocyte Serine Palmitoyltransferase 3 is essential for mitochondrial ceramide homeostasis and electron transport chain function. 肝细胞丝氨酸棕榈酰基转移酶3对线粒体神经酰胺稳态和电子传递链功能至关重要。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-09 DOI: 10.1016/j.jbc.2026.113630

Maryam Jamil, Anna Kovilakath, Yolander Valentine, Saaid Farooq, David Montefusco, Yang Yue, Gisela Beutner, Qun Chen, Jeremy Thompson, Komuraiah Myakala, Xiaoxin Wang, Christiane Carter, Jinze Liu, Arjun Rijal, Charles E Lyons, Devanand Sarkar, Moshe Levi, George A Porter, Sushil Mahata, Tytus Bernas, Edward J Lesnefsky, L Ashley Cowart

{"title":"Hepatocyte Serine Palmitoyltransferase 3 is essential for mitochondrial ceramide homeostasis and electron transport chain function.","authors":"Maryam Jamil, Anna Kovilakath, Yolander Valentine, Saaid Farooq, David Montefusco, Yang Yue, Gisela Beutner, Qun Chen, Jeremy Thompson, Komuraiah Myakala, Xiaoxin Wang, Christiane Carter, Jinze Liu, Arjun Rijal, Charles E Lyons, Devanand Sarkar, Moshe Levi, George A Porter, Sushil Mahata, Tytus Bernas, Edward J Lesnefsky, L Ashley Cowart","doi":"10.1016/j.jbc.2026.113630","DOIUrl":"10.1016/j.jbc.2026.113630","url":null,"abstract":"Sphingolipids constitute essential membrane lipids that also function as signaling molecules mediating fundamental cellular processes. Disruption of constitutive sphingolipid metabolism contributes to a range of metabolic diseases. Sphingolipid biosynthesis is initiated by serine palmitoyltransferase (SPT), a heteromeric enzyme composed of Sptlc1 and either Sptlc2 or the less-characterized subunit Sptlc3. While the canonical Sptlc1/Sptlc2 complex generates most sphingolipids, Sptlc1/Sptlc3 produces non-canonical sphingolipids that remain poorly understood. Sptlc3 expression increases in liver disease in both mouse models and humans, yet its biological role remains unclear. To address this, we generated a liver-specific SPTLC3 knockout (SPT3-hKO) mouse model. Loss of SPTLC3 resulted in severe mitochondrial dysfunction in hepatocytes, characterized by reduced oxygen consumption, decreased ATP production, and elevated NADH/NAD+ ratios with a concomitant increase in glycolytic activity. Mechanistically, we found a defect in the electron transport chain (ETC) which stemmed not from intrinsic impairment of the ETC complexes but rather from hindered electron flow between complex I and complex III likely due to reduced availability of Coenzyme Q. While atypical ceramides constituted (∼4% of total ceramides) when measured in liver homogenates, there measurements in mitochondria-enriched fractions revealed enrichment in this cell compartment. Together, our findings identify SPTLC3 as a critical modulator of mitochondrial ceramide composition and ETC function, revealing a specialized role for non-canonical sphingolipids in hepatocyte energy metabolism.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113630"},"PeriodicalIF":4.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148376","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

Strigolactones and antifungals induce internalization of major facilitator superfamily transporters. 独脚内酯类和抗真菌类诱导主要促进剂超家族转运蛋白的内化。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-09 DOI: 10.1016/j.jbc.2026.113631

George Ly, James M Bradley, Freddie R Montague, Michael Bunsick, Christopher S P McErlean, Peter McCourt, Dario Bonetta, Shelley Lumba

{"title":"Strigolactones and antifungals induce internalization of major facilitator superfamily transporters.","authors":"George Ly, James M Bradley, Freddie R Montague, Michael Bunsick, Christopher S P McErlean, Peter McCourt, Dario Bonetta, Shelley Lumba","doi":"10.1016/j.jbc.2026.113631","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113631","url":null,"abstract":"The major facilitator superfamily (MFS) is a diverse class of selective transporters that move a range of substrates across membranes. Despite their central role in cellular homeostasis, chemically perturbing MFS transporters is challenging. Here, we elucidate how the plant hormone, strigolactone (SL), internalizes the yeast MFS phosphate transporter, Pho84, and discover that the agricultural fungicide, chlorothalonil, also interacts with the SL allosteric binding site to cause Pho84 internalization. This piggybacking mechanism for chlorothalonil not only has agricultural applications but also explains why yeast MFS deletion lines show decreased sensitivity to various small molecule perturbagens. Deletion of the MFS inositol transporter, ITR1, for example, results in resistance to specific antifungal azoles. We demonstrate that the Itr1 protein is internalized by these antifungals. These findings propose a new paradigm by which small molecules regulate MFS trafficking and offer new insights to identify drugs targeting MFS transporters.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113631"},"PeriodicalIF":4.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149149021","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 cysteine-rich domain of SEP15, a selenoprotein co-chaperone of the ER chaperone, UDP-glucose:glycoprotein glucosyltransferase, adopts a novel fold. SEP15富含半胱氨酸的结构域，ER伴侣的硒蛋白共同伴侣，udp -葡萄糖：糖蛋白葡萄糖基转移酶，采用了一种新的折叠。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-09 DOI: 10.1016/j.jbc.2026.113629

Robert V Williams, Kevin P Guay, Owen Hurlbut Lesk, Daniel N Hebert, Lila M Gierasch

{"title":"The cysteine-rich domain of SEP15, a selenoprotein co-chaperone of the ER chaperone, UDP-glucose:glycoprotein glucosyltransferase, adopts a novel fold.","authors":"Robert V Williams, Kevin P Guay, Owen Hurlbut Lesk, Daniel N Hebert, Lila M Gierasch","doi":"10.1016/j.jbc.2026.113629","DOIUrl":"10.1016/j.jbc.2026.113629","url":null,"abstract":"Proteins targeted to the secretory pathway are involved in a myriad of biological processes but can only do so when properly folded. Within the endoplasmic reticulum, glycoprotein folding is regulated by the enzyme UDP-glucose:glycoprotein glucosyltransferase (UGGT) and its oxidoreductase partner, the 15-kDa selenoprotein (SEP15 aka SELENOF). The interaction between these two chaperones is poorly understood, limiting understanding of their function. SEP15 is comprised of two domains, a C-terminal thioredoxin-like domain, the structure of which has been reported (PDB 2A4H), and an approximately 50-residue long N-terminal cysteine-rich domain (CRD), of unknown structure. Here, we report the NMR solution structure of SEP15 CRD, which mediates the interaction with UGGT. These data reveal that this domain adopts a dimer in solution and forms a previously undescribed helical fold, stabilized by three disulfide bonds between residues C10-C42, C21-C43, and C24-C39. Furthermore, our results validate a model of the UGGT/SEP15 complex and lay the foundation for future studies of its interaction with glycoprotein substrates.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113629"},"PeriodicalIF":4.0,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149148412","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

Reading the Lipid Code: Cooperative Domain Functions in Perilipin Targeting to Lipid Droplets. 读取脂质代码：Perilipin靶向脂滴的协同结构域功能。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-08 DOI: 10.1016/j.jbc.2026.113619

Jiri Stribny, Roger Schneiter

{"title":"Reading the Lipid Code: Cooperative Domain Functions in Perilipin Targeting to Lipid Droplets.","authors":"Jiri Stribny, Roger Schneiter","doi":"10.1016/j.jbc.2026.113619","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113619","url":null,"abstract":"Perilipins (PLINs) are the most abundant proteins coating the phospholipid monolayer of lipid droplets (LDs), regulating their biogenesis, stability, growth, and lipolysis. Most mammalian isoforms (PLIN1-3, PLIN5) share a modular architecture characterized by an N-terminal PAT domain (perilipin-adipophilin-TIP47), a central 11-mer repeat region forming amphipathic helices (hydrophobic and hydrophilic faces on opposite sides of the helix), and a C-terminal 4-helix bundle; PLIN4 is a notable exception that relies mainly on expanded amphipathic helices. In this review, we synthesize recent structural, biophysical, and cell-biological advances and present a working framework in which these domains function cooperatively to read a local lipid code composed of diacylglycerol (DAG) enrichment, phospholipid composition, packing defects, and surface tension. The PAT domain preferentially engages DAG-rich endoplasmic reticulum (ER) subdomains to initiate recruitment and support LD budding. The 11-mer amphipathic helices, often weakly hydrophobic and highly repetitive, especially in PLIN4, recognize lipid packing defects and enable dynamic, tension-responsive binding, with polar residues supporting multimeric assembly and exceptional stability on LD surfaces. The C-terminal 4-helix bundle contains a conserved hydrophobic cleft that can accommodate phosphatidylethanolamine (PE); isolated domains prefer PE-rich interfaces, and PE limitation reduces cellular recruitment. Isoform-specific variations, including PLIN1's integral membrane segment for ER insertion and high-affinity binding, contribute to hierarchical sorting and LD heterogeneity. Together, these cooperative domain functions integrate lipid cues to orchestrate LD assembly and remodeling, with implications for metabolic diseases such as metabolic dysfunction-associated steatotic liver disease, obesity, and lipodystrophies.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113619"},"PeriodicalIF":4.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136780","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

Transcriptomic analysis uncovers dysregulated glycosylation pathways in clear cell renal cell carcinoma. 转录组学分析揭示透明细胞肾细胞癌中失调的糖基化途径。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-08 DOI: 10.1016/j.jbc.2026.113620

Ru M Wen, G Edward W Marti, Rosalie Nolley, Nathan Lam, Hongjuan Zhao, Donna M Peehl, James D Brooks

{"title":"Transcriptomic analysis uncovers dysregulated glycosylation pathways in clear cell renal cell carcinoma.","authors":"Ru M Wen, G Edward W Marti, Rosalie Nolley, Nathan Lam, Hongjuan Zhao, Donna M Peehl, James D Brooks","doi":"10.1016/j.jbc.2026.113620","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113620","url":null,"abstract":"Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer and is characterized by altered metabolism, immune remodeling, and aberrant glycosylation. Although glycosylation regulates tumor-cell signaling, adhesion, angiogenesis, and immune recognition, its relationship with the ccRCC immune microenvironment remains incompletely defined. Here, we analyzed RNA-sequencing profiles from ccRCC tumors and adjacent normal kidney tissues. Glycan-related genes and glycogenes involved in glycan biosynthesis distinguished ccRCC tumors from normal tissues and revealed altered sulfatase, nucleotide sugar, glycosyltransferase, glycosaminoglycan pathways. CIBERSORTx analysis showed distinct immune cell distributions in tumors, and Spearman correlation analysis linked glycosylation pathway activity with immune cell abundance. Glycogene expression further classified ccRCC tumors into two subtypes with different immune signatures, Siglec expression patterns, and overall survival. The transcriptional differences between normal and tumor tissues are dominated by immune/inflammatory activation and ion/membrane transport regulation. Our results underscore the importance of targeting cancer-associated changes in glycosylation machinery using novel strategies to improve the specificity and efficacy of cancer therapeutics in ccRCC.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113620"},"PeriodicalIF":4.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136862","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

Microtubule destabilization by SB225002 through preferential weakening of lateral tubulin interactions revealed by structural and computational analyses. 结构和计算分析揭示了SB225002通过优先削弱侧微管相互作用来破坏微管的稳定性。

IF 4 2区生物学

Journal of Biological Chemistry Pub Date : 2026-10-08 DOI: 10.1016/j.jbc.2026.113625

Xinyao Liu, Cuiyu Guo, Yuxi Wang, Dongsheng Lei

{"title":"Microtubule destabilization by SB225002 through preferential weakening of lateral tubulin interactions revealed by structural and computational analyses.","authors":"Xinyao Liu, Cuiyu Guo, Yuxi Wang, Dongsheng Lei","doi":"10.1016/j.jbc.2026.113625","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113625","url":null,"abstract":"Microtubules are essential for cell division and intracellular signaling, making them well-established targets for anticancer therapy. However, the clinical utility of conventional microtubule-targeting agents is often limited by toxicity and drug resistance. SB225002, originally identified as an interleukin-8 receptor antagonist, has been reported to disrupt microtubule dynamics and exhibit anticancer activity with relatively low toxicity in preclinical studies. Yet, the structural basis of its interaction with tubulin remains poorly understood. Here, we determined the crystal structure of the SB225002-tubulin complex at 2.60 Å resolution and performed molecular dynamics simulations to characterize ligand binding, as well as drug-induced changes in tubulin structure and inter-subunit interactions. The crystal structure revealed three SB225002 molecules occupying the colchicine- and vinblastine-binding regions of tubulin. Simulations showed persistent ligand association over the simulated timescale and relatively limited overall changes in longitudinal inter-subunit interactions, whereas structural flexibility and dynamic coupling were preferentially altered at the lateral-interface-associated surface of β-tubulin. Additional simulations incorporating both lateral and longitudinal tubulin interfaces further revealed a greater reduction in lateral than in longitudinal inter-subunit contacts upon drug binding. Together, these results support a mechanism in which SB225002 preferentially perturbs lateral tubulin interactions and provide a structural framework for understanding its microtubule-modulating activity.","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113625"},"PeriodicalIF":4.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136682","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