Journal of Biological Chemistry最新文献

{"title":"Pattern recognition receptors and divergent disease severity in zoonotic viral infections.","authors":"Daniel S Mansur, Brooke Trowbridge, José Henrique M Oliveira, Rodrigo Guabiraba, Brian J Ferguson","doi":"10.1016/j.jbc.2026.113618","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113618","url":null,"abstract":"<p><p>Zoonotic viruses continue to emerge unpredictably, cross species barriers, and inflict major health, economic, and ecological burdens. Recent outbreaks of SARS-CoV-2, H5N1 avian influenza virus (AIV), monkeypox, and Zika virus underscore the unpredictability of viral emergence and the urgent need to understand host/pathogen interactions. This review focuses on how innate immune sensing via pattern recognition receptors (PRRs) shapes disease severity across different species. While PRRs initiate antiviral defenses (interferons, ISGs), inflammatory cytokines, and programmed cell death, host outcomes diverge widely, shaped by genetic variation in PRR pathways and their regulators. Dysregulated inflammatory responses and inflammatory cell death can contribute substantially to severe disease independently of viral load, as demonstrated in influenza and coronavirus infections. Viral effectors that suppress or alter PRR signaling can show species-specific efficacy, and these mismatches can be critical determinants of disease when viruses jump hosts. Using avian influenza as an example, we highlight how disease outcomes vary with viral strain, host species, response timing, and tissue context. Overall, we propose that differential disease severity across host species reflects the balance among PRR-mediated resistance, the efficiency of viral immune evasion in the relevant host, and innate disease-tolerance mechanisms that limit tissue damage. Understanding these dynamics could enhance our ability to predict zoonotic emergence and mitigate the impact of viral pandemics.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113618"},"PeriodicalIF":4.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136819","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}

{"title":"Structural basis for oxidation-coupled isomerization by ApnO.","authors":"Seiya Watanabe, Yuzuki Aono, Shin-Ichi Terawaki, Himika Sato, Taiyo Yokoi","doi":"10.1016/j.jbc.2026.113628","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113628","url":null,"abstract":"<p><p>D-Apionate oxidoisomerase (ApnO), involved in D-apiose metabolism from bacteria, is one of the few examples of the enzymes that catalyze two different reactions within a single active site, whereas there is no functional orthologue with significant sequence identity. Based on genome context, we found that ApnO additionally utilizes D-erythronate and D-ribonate as substrates, which made it possible to functionally characterize the enzyme. Crystallographic studies (using anomalous dispersion analysis) revealed that the overall folding of ApnO was similar to that of ketol-acid reductoisomerase (KARI), with two magnesium ions at sites II and I, and that the purified (inactive) enzyme contained one zinc ion at site II (and NAD⁺). Further crystallization in the presence of manganese ion led to the binding of manganese ions at both sites II and I. Among them, the coordination geometry at site II was uniquely tetrahedral, differed from the typical octahedral geometry observed at site I. Several crystal structures in complex with malonate and/or its derivative inhibitor, together with substrate docking simulations, showed a mechanism of oxidation-coupled isomerization similar to that of KARI via a cyclopropane transition state, whereas only four active site residues around the metal ion binding site I were conserved between ApnO and KARI, suggesting that they convergently acquired the second metal ion binding site (site II) in evolutional stage.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113628"},"PeriodicalIF":4.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136826","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}

{"title":"Systematic mapping of chimera-permissive sites by CRISPR-guided PAM scanning.","authors":"Jacinda Pujols, Kyutae D Lee, Nick J Kapolka, Sam Taylor, Bruno Colon, Daniel G Isom","doi":"10.1016/j.jbc.2026.113627","DOIUrl":"10.1016/j.jbc.2026.113627","url":null,"abstract":"<p><p>Protein chimeras enable new biological functions by combining otherwise independent protein elements, but identifying insertion sites that preserve host protein function remains largely empirical. Here, we introduce CRISPR-guided protospacer adjacent motif (PAM) scanning, a scalable strategy for mapping chimera-permissive sites directly in living cells. PAM scanning uses CRISPR-addressable positions across coding sequences to systematically install functional payloads and measure insertion tolerance. In yeast, PAM accessibility provided near-comprehensive coverage across proteins of diverse size and function. We first applied this approach across an entire G protein-coupled receptor (GPCR) signaling pathway, generating 91 chimeras containing inserted protease recognition sequences to map insertion tolerance and site-specific biophysical protection from a protease probe by surrounding protein structure and binding partners. Cognate protease cleavage revealed how this protection varied with protease inhibition and size. We then used PAM scanning to identify bi-functional GPCR chimeras that retained receptor signaling while supporting fluorescent or luminescent reporters. Screening human adenosine A2A and melatonin MTNR1A receptors in yeast identified functional mNeonGreen and NanoLuc insertion sites that retained ligand-dependent signaling following translation to human cells. Together, these studies establish PAM scanning as a general framework for mapping insertional tolerance and biophysical protection in living cells, accelerating functional chimera engineering, and experimentally validating generative chimera design.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113627"},"PeriodicalIF":4.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136872","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}

{"title":"TRPM2 couples cell-autonomous type-I interferon signaling to pigmentation homeostasis.","authors":"Nutan Sharma, Abhishek Tanwar, Changyu Zheng, Indu Ambudkar, Rajender K Motiani","doi":"10.1016/j.jbc.2026.113624","DOIUrl":"10.1016/j.jbc.2026.113624","url":null,"abstract":"<p><p>Transient Receptor Potential Melastatin 2 (TRPM2), a Ca²⁺-permeable cation channel, regulates innate and adaptive immunity and has recently been implicated in vitiligo, an autoimmune pigmentary disorder. However, whether TRPM2 exerts cell-autonomous immunoregulatory functions and how such signaling intersects with pigmentation remain unknown. Here, we reveal an unexpected role for TRPM2 as an intrinsic suppressor of pigmentation through type-I interferon (IFN) signaling in melanocytes. Pharmacological inhibition, genetic silencing, and gain-of-function approaches demonstrate that TRPM2 negatively regulates melanogenesis in vitro. Notably, TRPM2-deficient zebrafish and TRPM2^-/^- mice exhibit enhanced pigmentation in vivo, establishing physiological relevance. Transcriptomic profiling uncovers autonomous activation of the type-I-IFN pathway upon TRPM2 loss, leading to induction of IFN-stimulated gene 15 (ISG15). Mechanistically, ISG15 attenuates global ubiquitination and stabilizes microphthalmia-associated transcription factor (MITF), the master regulator of melanogenesis, thereby promoting pigmentation. Collectively, our findings define a previously unrecognized TRPM2-type-I-IFN-ISG15-MITF signaling axis that functionally integrates cell-autonomous immune surveillance pathways with pigmentary control. Further, it provides a conceptual framework linking type-I-IFN signaling to pigmentation homeostasis and pigmentary disorders.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113624"},"PeriodicalIF":4.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136869","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}

{"title":"Heme-Proximal Loop Dynamics Modulate Mn(II) Oxidation in Pseudomonas putida MET94 DyP-type peroxidase.","authors":"Carolina F Rodrigues, Constança Lorena, Tomás Frazão, Vânia Brissos, Patrícia T Borges, Lígia O Martins","doi":"10.1016/j.jbc.2026.113622","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113622","url":null,"abstract":"<p><p>Enzymatic Mn(II) oxidation is relevant to both natural lignin degradation and the development of new industrial biocatalysts. DyP-type peroxidases are versatile microbial biocatalysts with potential applications in lignocellulose valorization, but the structural features influencing their Mn(II)-oxidizing activity remain incompletely understood. We determined the X-ray crystal structure of PpDyP from Pseudomonas putida bound to Mn(II), identifying a heme-proximal Mn-binding environment defined by E135, E188, and E204 in loop regions surrounding the heme pocket. Mutagenesis and steady-state kinetics indicate that these residues cooperate to shape the Mn(II)-oxidation environment and support catalysis. We then examined the E209A variant, in which the non-coordinating residue E209, located near E204, was replaced by alanine. E209A increased apparent Mn(II)-oxidation turnover approximately fivefold. Structural analysis showed that E209A displaces E204 and rearranges Q203-mediated inter-loop contacts, supporting E204's structural contribution to organizing the heme-proximal loop environment. This rearrangement was associated with increased loop flexibility and greater heme exposure, supporting a more accessible and dynamically permissive heme-proximal architecture. A distal Mn(II)-binding site involving E237 and E240 was also observed in E209A, but mutational analysis suggests that it contributes mainly to residual activity when the heme-proximal site is perturbed. Finally, we show that Mn(II) oxidation by PpDyP markedly enhances the oxidation of lignin-relevant substrates, including 2,6-dimethoxyphenol, guaiacol, guaiacylglycerol-β-guaiacyl ether, and alkali lignin, by up to 100-fold. Together, these findings support loop-network modulation as a strategy to tune bacterial DyP peroxidases for lignin valorization and oxidative biotransformations.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113622"},"PeriodicalIF":4.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136726","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}

{"title":"Ion Channel Nano-Diagnostics for ER+ Breast Cancer.","authors":"Manos Gkikas, Evangelos Dadiotis, Mehreen Zaka, Nihal Aly, Kim Chan, Diomedes E Logothetis","doi":"10.1016/j.jbc.2026.113623","DOIUrl":"10.1016/j.jbc.2026.113623","url":null,"abstract":"<p><p>Ion channels are pore-forming transmembrane proteins that allow ions to move down an electrochemical gradient and across the channel pore and regulate many cell functions. Among them, are the G-protein-gated inwardly-rectifying K+ channels 1 (GIRK1) that are ubiquitously expressed with major functions in the brain and heart. Interestingly, significantly higher GIRK1 expression has been found in estrogen receptor positive (ER+) breast cancer patients compared to patients with HER2+ tumors or normal patients, and that was statistically correlated with shorter survival times and metastatic potential. Herein, we report the preparation of a ∼4 nm GAT1508-coated poly(ethylene glycol) gold nanoparticle (PEGylated AuNP) biomarker for ER+ breast cancer cell screening through an optical microscope. A urea-based small molecule, GAT1508, with an N-methylpyrazole benzyl group on its head and a bromo-thiophene on its tail, has been shown to predominantly bind GIRK1 subunits and specifically activate GIRK1/2 channels. Two derivatives of GAT1508 were synthesized and characterized: an ethylamine derivative (GAT1508-EA) with a chain extension from the benzyl ring, and a propylamine derivative (GAT1508-PA) with a chain extension from the pyrazole ring. Electrophysiology (TEVC and whole-cell patch-clump) experiments as well as fluorescence studies (Thallium assay) showed that only GAT1508-PA inhibited GIRK1/2-mediated K+ currents in transfected HEK293^GIRK1 cells. Docking studies showed strong binding for the propylamine GAT1508 derivative, both in the amine form (GAT1508-PA) as well as in the amide form (GAT1508-PA-EG2; coupled with PEG as in the AuNPs). GAT1508-PEG-AuNPs (GAT1508-NPs) were synthesized subsequently with ∼65 wt% metal loading. UV-Vis studies revealed the presence of the conjugated ligand at 260 nm. Flow cytometry studies showed binding of Alexa 594-labeled GAT1508-NPs in ER+ MCF-7 breast cancer cells with a strong interaction, while incubation of fixed MCF-7 cells with a GAT1508-NP solution led to optical detection of ER+ breast cancer cells, without the need of fluorescent dyes and additional amplification steps. Detection was not feasible in MDA-MB-231 cells, a triple (-) breast cell line that does not express GIRK1. This, to our knowledge, is the first study that couples nanotechnology with small molecule drug design and electrophysiology to develop ion channel-tracing molecular probes for the detection/screening of ER+ breast cancer.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113623"},"PeriodicalIF":4.0,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149136710","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}

{"title":"The mechanism of R2ab-mediated attachment to polystyrene surfaces in Staphylococcus epidermidis.","authors":"Rahul Yadav, Y Randika Perera, Radha P Somarathne, Himanshi Shorie, Soneika Carby, Archana Mishra, Nicholas C Fitzkee","doi":"10.1016/j.jbc.2026.113533","DOIUrl":"10.1016/j.jbc.2026.113533","url":null,"abstract":"<p><p>The staphylococcal autolysin protein hydrolyzes cell wall peptidoglycans. The R2ab repeats of autolysin guide the catalytic domain by binding to cell wall components and mediate attachment to abiotic surfaces during biofilm formation on polystyrene. Characterizing protein interactions with surfaces is a significant challenge in understanding bacterial attachment. Here, using nuclear magnetic resonance spectroscopy, we determined the solution structure and backbone dynamics of the R2ab domain. We then, by combining nuclear magnetic resonance and calorimetry, identified the interaction mode of R2ab with cell wall components and polystyrene surfaces. The solution-derived R2ab structure reveals interaction surfaces with lipoteichoic acid and peptidoglycan. The binding regions are identified, and docking is used to model their binding to R2ab. R2ab also interacts with polystyrene nanoparticles. Using a novel approach where polystyrene nanoparticles are paramagnetically labeled, we identify the major R2ab-polystyrene interaction interface. R2ab engages polystyrene surfaces via a defined C-terminal interface on R2b, as revealed by PRE mapping, isothermal titration calorimetry, and mutational analyses. Polar and charged residues (notably S776 and K779) play key roles in adsorption. These findings support a model in which R2ab acts as a molecular bridge, binding both cell wall components and abiotic surfaces. This highlights its role in early biofilm formation and suggests that disrupting this interaction could reduce Staphylococcus epidermidis attachment to abiotic surfaces.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113533"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13677396/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The lariat RNA debranching enzyme DBR1 enhances HIF-1 signaling and chemoresistance at the expense of lariat RNA processing.","authors":"Phuong Thi Lien Nguyen, Minoru Kobayashi, Sho Koyasu, Kumi Johchi, Hiroshi Harada","doi":"10.1016/j.jbc.2026.113484","DOIUrl":"10.1016/j.jbc.2026.113484","url":null,"abstract":"<p><p>Severely hypoxic microenvironments that induce cell-cycle arrest and chemoresistance are frequently found within solid tumors. Since hypoxia-inducible factor 1 (HIF-1) serves as a central transcription factor for cellular adaptation to oxygen deprivation, identification of novel regulators of HIF-1 activity may provide novel therapeutic opportunities. Here, we performed a genome-wide screening for novel positive regulators of HIF-1 and identified debranching RNA lariats 1 (DBR1). DBR1 was found to form a complex with the regulatory subunit of HIF-1, HIF-1α, promote its nuclear accumulation and recruitment to hypoxia-response elements, and enhance HIF-1-dependent transcription without altering HIF1A mRNA or protein levels. Notably, a catalytic mutant of DBR1 lacking debranching activity retained the ability to activate HIF-1. Interestingly, under hypoxic conditions, HIF-1 redirected DBR1 from its canonical RNA debranching function toward HIF-1-dependent transcriptional regulation, resulting in reduced debranching activity, lariat RNA accumulation, and impaired cell growth. Furthermore, DBR1 contributed to hypoxia-induced resistance to multiple conventional chemotherapeutic agents. Collectively, our findings support a model in which HIF-1 functionally redistributes DBR1 from lariat RNA processing toward HIF-1-dependent transcription, thereby promoting HIF-1 signaling and chemoresistance at the expense of lariat RNA processing.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113484"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13629192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response.","authors":"Nathan A Snyder, Gustavo M Silva","doi":"10.1016/j.jbc.2026.113504","DOIUrl":"10.1016/j.jbc.2026.113504","url":null,"abstract":"","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"302 10","pages":"113504"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Structures of human protein tyrosine phosphatase variants reveal targetable allosteric sites.","authors":"Aliki Perdikari, Virgil A Woods, Ali Ebrahim, Katherine Lawler, Rebecca Bounds, Dinesh S Shah, Nathanael I Singh, Tamar Skaist Mehlman, Blake T Riley, Shivani Sharma, Jackson W Morris, Julia M Keogh, Elana Henning, Miriam Smith, I Sadaf Farooqi, Daniel A Keedy","doi":"10.1016/j.jbc.2026.113502","DOIUrl":"10.1016/j.jbc.2026.113502","url":null,"abstract":"","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":"302 10","pages":"113502"},"PeriodicalIF":4.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13631572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149016836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}