Journal of Biological Chemistry最新文献

{"title":"Structural and Kinetic Basis for Selective Inhibition of Canine Myeloperoxidase by Staphylococcal Peroxidase Inhibitor (SPIN) Orthologs.","authors":"Soheila Fatehi, Timothy J Herdendorf, Amy Burklund, Trisha Kvasnica, Elizabeth Lindquist, Hatem Kittana, Brian V Geisbrecht","doi":"10.1016/j.jbc.2026.113649","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113649","url":null,"abstract":"<p><p>Staphylococcus aureus and related species are highly adapted to their hosts and have evolved numerous strategies to evade the innate immune system. The Staphylococcal Peroxidase Inhibitor (SPIN) is a small, secreted protein that inhibits myeloperoxidase (MPO). SPIN blocks the MPO active site and prevents production of cytotoxic hypohalous acids within the neutrophil phagosome, thereby enabling evasion of oxidative killing. S. aureus is primarily a human pathogen, and its SPIN protein cannot inhibit MPO from most non-human species. This raises questions as to whether staphylococci adapted to alternative mammalian hosts might produce SPIN proteins with similarly strict preferences for MPO from those species. We tested this hypothesis by isolating canine MPO (cMPO) from abscess samples obtained for veterinary diagnostic purposes and exploring its inhibition profile by a panel of SPIN orthologs. Across two independent trials, SPIN proteins from known canine pathogens bound to and inhibited canine MPO (cMPO) much more potently than human MPO (hMPO). We also found that this increased affinity and potency arises from corresponding increases in the association rate constant (k_a) rate constant for cMPO as compared to hMPO. A 2.10 Å resolution co-crystal structure of cMPO inhibited by SPIN from S. delphini provided insights into the physical basis for our functional observations. Along our previous studies on the SPIN/MPO interaction, this work lays a foundation for broadly defining the structure/function principles that underlie host-specific evolution of immune evasion proteins.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113649"},"PeriodicalIF":4.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182091","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":"EPG5 orchestrates iron compartmentalization through dual regulation in macroferritinophagy.","authors":"Yilun Chen, Yi Yang, Rui Wang, Hanyu Wang, Chunyan Wu, Qun Lu","doi":"10.1016/j.jbc.2026.113646","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113646","url":null,"abstract":"<p><p>Intracellular iron is distributed across functionally distinct pools though the mechanisms regulating its compartmentalization remain unclear. Here we show that EPG5, a tethering factor required for autophagosome-lysosome fusion, governs iron compartmentalization through dual mechanisms: direct involvement in autophagy and indirect regulation of ferritinophagy initiation. A systematic comparison of autophagy genes indicates that EPG5 deficiency uniquely decreases hemosiderin and increases the labile iron pool, a profile distinct from ATG5, ATG14, FIP200, or WDR45 deficiencies. Mechanistically, EPG5 loss disrupts autophagosome maturation and endocytic trafficking, causing ferritin condensates and iron transporters to accumulate in aberrant autophagosomes and endosomes. This blockade triggers compensatory TBK1 activation. TBK1 subsequently phosphorylates TAX1BP1 and interacts with the ferritinophagy receptors NCOA4, inhibiting receptor homo-oligomerization and modulating ferritinophagic flux. These findings position EPG5 as a novel orchestrator of iron compartmentalization and highlight the role of TBK1-NCOA4/TAX1BP1 axis in iron homeostasis and related stress response.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113646"},"PeriodicalIF":4.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181465","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":"An m⁷G tRNA-derived fragment mediated thermogenic activation of brown adipose tissue through post-transcriptional repression of Uqcr10.","authors":"Xue Zhao, Mailin Gan, Xingyu Wang, Yidong Chen, Jiaqi Zhu, Qing Ye, Jincheng Zan, Yuhang Lei, Xiaofeng Zhou, Lei Chen, Ye Zhao, Li Zhu, Yan Wang, Linyuan Shen","doi":"10.1016/j.jbc.2026.113640","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113640","url":null,"abstract":"<p><p>Obesity, diabetes, and related metabolic disorders have become global epidemics driven mainly by an imbalance between energy intake and energy expenditure. Brown adipose tissue (BAT), the principal site of non-shivering thermogenesis, can be activated to mitigate obesity and its metabolic sequelae. RNA modification is as important regulators of obesity. The N7-methylguanosine (m⁷G) modification broadly influences RNA stability, enhances translational efficiency, and helps determine cell fate. However, the specific mechanisms by which m⁷G regulates adipose thermogenesis remain unclear. Using untargeted metabolomics, we found that cold exposure activates thermogenic metabolism in BAT and that 7-Methylguanosine is elevated in thermogenically activated BAT. METTL1-mediated m⁷G modification correlates positively with adipose thermogenic activation. Loss of METTL1 reduces m⁷G levels and impairs adipocyte thermogenic capacity. At the same time, METTL1 deficiency alters tRNA cleavage patterns and generates regulatory tRNA-derived fragments that modulate gene expression. Overexpression of tRF-Lys-CTT, which derives from an m⁷G-modified tRNA, inhibits brown adipocyte differentiation and thermogenic activation; conversely, inhibiting tRF-Lys-CTT produces the opposite effects. Mechanistically, tRF-Lys-CTT associates with AGO2 to form a functional RISC complex that binds the 3'UTR of Uqcr10 mRNA and directly represses Uqcr10 post-transcriptionally. Under basal conditions, elevated tRF-Lys-CTT may constrain mitochondrial function by repressing Uqcr10 expression; upon cold stimulation, downregulation of tRF-Lys-CTT relieves this repression and promotes respiratory chain supercomplex assembly and UCP1-mediated thermogenesis. In summary, our study indicates that tRF-Lys-CTT functions as a post-transcriptional regulator of metabolism that suppresses thermogenesis, and provides new insights into the regulatory relationship among the METTL1/m⁷G/tRF axis and thermogenic control.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113640"},"PeriodicalIF":4.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182032","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":"Differential histone tail citrullination by protein arginine deiminases observed via NMR spectroscopy.","authors":"Alex J Kowalczyk, Emma A Morrison","doi":"10.1016/j.jbc.2026.113639","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113639","url":null,"abstract":"<p><p>Citrullination is a charge-modifying post-translational modification whereby proteinogenic arginine is converted to the non-coded amino acid citrulline by calcium-activated protein arginine deiminases (PADs; EC 3.5.3.15). The five known PAD enzymes in humans (PADs 1, 2, 3, 4, and 6) are differentially expressed and have distinct protein targets, including histones. While some PAD histone citrullination sites are known, a comprehensive investigation of all histone tail arginines targeted by catalytically active PADs 1-4 is lacking. Here, we sought to identify PAD citrullination sites in histone tails, within both histone peptides and reconstituted nucleosomes. Toward this objective, we utilized a real-time ¹H-¹⁵N NMR spectroscopy-based assay. By monitoring both arginine and citrulline backbone amide peak intensities over time, we identified sites of citrullination in ¹⁵N-labeled histone tails within peptides and reconstituted nucleosome core particles. We found that PADs 1, 2, and 4 citrullinate all directly observable histone tail arginines to varying degrees. This is distinct from PAD3, which only moderately citrullinates H2A and H4 arginine residues and does not modify H3 tail arginines. Together, these data suggest a level of histone arginine specificity by each PAD. Furthermore, histone tail citrullination is altered within nucleosomes as compared to isolated peptides, which we interpret as reflecting differences in conformation and accessibility. We also speculate that citrullination increases nucleosomal histone tail dynamics, with implications for crosstalk between sites of histone citrullination and other important sites of regulation by PTMs (including lysines) within and between tails.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113639"},"PeriodicalIF":4.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181293","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":"MYCBP ensures faithful chromosome segregation during mitosis by anchoring Astrin/SKAP to kinetochore.","authors":"Yujia Yang, Xinyang Wang, Xiuhong Hu, Haiyan Liu, Xing Liu, Xuebiao Yao, Xiwei Wang, Zhen Dou","doi":"10.1016/j.jbc.2026.113641","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113641","url":null,"abstract":"<p><p>Proper kinetochore-microtubule (KT-MT) attachment is essential for faithful chromosome segregation during mitosis. The Astrin complex, localized at the outer kinetochore, stabilizes proper KT-MT attachments to ensure accurate chromosome alignment and segregation. MYCBP has been identified as a subunit of the Astrin complex, yet its mitotic function remains poorly illustrated. Here, we show that MYCBP displays diffuse cytoplasmic and nuclear distribution in interphase, but concentrates at spindles and kinetochores during metaphase and anaphase. Knockdown of MYCBP in HeLa and HCT116 cells resulted in metaphase alignment defects, mitotic arrest, and anaphase bridges. MYCBP depletion did not alter total Astrin or SKAP protein levels, but markedly reduced their kinetochore localization and compromised KT-MT attachment stability. MYCBP physically interacts with Astrin/SKAP via its N-terminus and specifies their localization to kinetochore. Importantly, Disruption of MYCBP-SKAP interaction by either a membrane-permeable competing peptide or point mutation abrogates accurate chromosome segregation, which recapitulated the MYCBP knockdown phenotypes. These findings reveal a key role for the MYCBP-SKAP interaction in achieving a stable kinetochore-microtubule interaction essential for faithful chromosome segregation.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113641"},"PeriodicalIF":4.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182102","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 mechanism of TRPC3 inhibition by a potent antagonist.","authors":"Jodie Collingridge, Bethan A Cole, Molly A Rowlett, John Liddle, Kelly M Gatfield, Philip C Biggin, Ebe Becker","doi":"10.1016/j.jbc.2026.113644","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113644","url":null,"abstract":"<p><p>The transient receptor channel canonical family member 3 (TRPC3) is a non-selective, calcium-permeable cation channel within the larger TRP superfamily. TRPC3 is expressed in both excitable and non-excitable cells, where it integrates multiple signaling pathways and is directly activated by binding of diacylglycerol following activation of G-protein coupled receptors. Increased TRPC3 signaling is implicated in several diseases, highlighting TRPC3 as a potential therapeutic target. However, the development of TRPC3 inhibitors with suitable potency and selectivity has been challenging due to the channel's high structural and sequence homology with related family members, specifically TRPC6. Here, we present a highly potent TRPC3 antagonist (GSK2820986A) featuring an anilino-thiazole pharmacophore. Through a combination of molecular dynamic simulations and functional assays, we identify a putative binding site for GSK2820986A in the S4-S5 pocket and propose a potential inhibitory mechanism. Our findings provide a powerful tool compound and mechanistic framework to advance the investigation and therapeutic targeting of TRPC3.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113644"},"PeriodicalIF":4.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182116","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":"METTL10 trimethylation of eEF1A at K318 enhances protein synthesis and tumorigenesis.","authors":"Lauren Buie, Simone Hausmann, Juhyung Park, Sabeen Ikram, Tourkian Chasan, Xiaojie Yang, Natasha M Flores, Pawel Mazur, Or Gozani","doi":"10.1016/j.jbc.2026.113635","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113635","url":null,"abstract":"<p><p>eEF1A is an essential non-ribosomal translation elongation factor that mediates the high-fidelity delivery of aminoacyl-tRNAs to elongating ribosomes. Like histone H3, eEF1A undergoes extensive lysine methylation, with five distinct residues targeted by dedicated lysine methyltransferases (KMTs). However, compared with histone methylation, relatively little is known about the molecular and physiological functions of eEF1A lysine methylation. Here, we focus on METTL10, the KMT that catalyzes trimethylation of eEF1A at lysine 318 (eEF1AK318me3). We show that the METTL10-eEF1AK318me3 axis modestly enhances global protein synthesis and supports pancreatic ductal adenocarcinoma (PDAC) tumorigenesis in vivo. We identify the 236 amino-acid isoform as the catalytically active endogenous form of METTL10 and demonstrate that it is required for eEF1AK318me3 generation in multiple human cell lines. Further, we provide evidence that eEF1AK318 is the principal physiologic target of METT10. Loss of eEF1AK318 modestly reduces global protein synthesis across multiple cancer cell lines without substantially impacting polysome formation. METTL10 depletion attenuates proliferation of multiple cancer cell lines, an effect that depends on its catalytic activity. Moreover, elevated eEF1AK318me3 levels in PDAC tumors are associated with poor patient outcomes. Finally, METTL10 ablation attenuates tumor growth and extends survival in a KRAS^G12D-driven PDAC mouse model. Together, our work identifies the METTL10-eEF1AK318me3 axis as a regulator of protein synthesis and implicates it in PDAC pathogenesis.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113635"},"PeriodicalIF":4.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181889","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":"ATG13 Recruits LC3 to Target H9N2-IAV PB1 for Autophagic-Lysosomal Degradation and Restricts Viral Replication.","authors":"Yiyuan Lu, Huimin Xiao, Tianhao Liang, Haixu Wang, Jiarui Wang, Mingyang Cheng, Yu Sun, Enqi Dai, Ting Wang, Shaojie Wang, Zixuan Cao, Wentao Yang, Yanlong Jiang, Guilian Yang, Jianzhong Wang, Hanwei Jiao, Xin Cao, Chunfeng Wang, Junyan Li, Yan Zeng","doi":"10.1016/j.jbc.2026.113637","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113637","url":null,"abstract":"<p><p>Autophagy-related protein 13 (ATG13) is a critical component of the autophagy initiation complex and plays a pivotal role in regulating the initiation of autophagy. However, the precise mechanism by which ATG13 modulates influenza A virus (IAV) replication remains unclear. In this study, we demonstrated that ATG13 specifically interacts with the viral polymerase basic protein 1 (PB1) of H9N2-IAV and facilitates the autophagic degradation of PB1. Mechanistically, ATG13 targeted the C-terminal domain of PB1 and recruits microtubule-associated protein 1 light chain 3 (LC3) to promote the autophagolysosomal degradation of PB1. This process counteracts the PB1-mediated degradation of mitochondrial antiviral signaling protein (MAVS), thereby attenuating the immune evasion capacity of H9N2-IAV and ultimately suppressing viral replication. Collectively, our findings unveil for the first time a molecular mechanism whereby ATG13 negatively regulates IAV replication by mediating the targeted degradation of PB1 via the autophagolysosomal pathway. This study reveals a novel role of the autophagy pathway in host antiviral defense and provides a potential therapeutic target for anti-influenza agents.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113637"},"PeriodicalIF":4.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149182094","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":"Four-stranded G4 DNA Formation During Synthesis Phase of the Cell Cycle Protects Human Cells from Radiation Induced DNA Breaks.","authors":"Susmita Kumari, Sayak Das, Chirag Panigrahi, Supriya V Vartak, Sumedha Dahal, Sathees C Raghavan","doi":"10.1016/j.jbc.2026.113643","DOIUrl":"https://doi.org/10.1016/j.jbc.2026.113643","url":null,"abstract":"<p><p>The breaks induced during exposure to ionizing radiation are generally random. However, some studies show differences in radioprotection among the species within the same genus due to factors like DNA repair efficiency, genome complexity, chromatin organization, etc. A recent study linked the formation of G4 structures to differential radiosensitivity of the human genome. The present study investigates whether radiation-induced DNA damage varies across different phases of the cell cycle and explores the molecular basis for this. Neutral comet and immunofluorescence assays demonstrated that cells in S phase exhibit significantly fewer IR-induced DSBs compared to those in G1 or G2/M phases. In contrast, S phase cells remained fully susceptible to DSB induction by ROS-independent clastogens, indicating that S phase radioprotection is linked to ROS mitigation rather than intrinsic structural resistance alone. BG4 immunofluorescence revealed a higher abundance of transient G4 structures in replicating S phase cells. Depleting the BLM helicase via shRNA stabilized these G4 structures and further suppressed IR-induced DSB accumulation during S phase. Biochemical analyses using the Amplex Red assay confirmed that G4 DNA efficiently quenches IR-generated ROS, whereas non-G4 DNA shows negligible scavenging activity. Quantitative PCR assays corroborated that G4-enriched genomic loci sustain substantially less radiation damage than non-G4 control regions across all cell-cycle phases. Collectively, these findings demonstrate that elevated G-quadruplex formation during DNA replication acts as an intrinsic ROS sink that shields the genome against radiation injury. Alongside robust homologous recombination repair, G4-mediated radioprotection drives cell-cycle-dependent radiation tolerance, highlighting a structural mechanism governing human genome integrity.</p>","PeriodicalId":15140,"journal":{"name":"Journal of Biological Chemistry","volume":" ","pages":"113643"},"PeriodicalIF":4.0,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149181673","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":"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":"<p><p>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 (PIGCY^Tg) did not reverse the abnormal Ca²⁺-sensitivity of RetGC in mice harboring Y99C GCAP1 (Y99C^Tg) but reduced the overall cGMP production rate in dark-adapted PIGCY^TgY99C^Tg retinas. PIGCY markedly slowed the progression of photoreceptor degeneration in Y99C^Tg mice: 84% of photoreceptor nuclei remained after 6 months in PIGCY^TgY99C^Tg compared with only 30% in Y99C^Tg littermates. The histological layer of rod outer segments in the posterior retina was much better defined in aged PIGCY^TgY99C^Tg mice than in Y99C^Tg littermates. Electroretinography (ERG) showed that PIGCY also dramatically rescued the light sensitivity of the dark-adapted Y99C^Tg rods. Whereas scotopic b-wave amplitude (rod ERG) diminished sixfold in Y99C^Tg compared with the wild type, it remained 80% of normal amplitude in PIGCY^TgY99C^Tg littermates. ERG a-wave amplitude, generated by hyperpolarizing photoreceptors in response to a bright flash, was reduced more than tenfold in Y99C^Tg but only by 35% in PIGCY^TgY99C^Tg. The results indicate that PIGCY can be considered for prospective gene therapy for some GCAP1 mutations causing dominant GUCA1A retinopathy.</p>","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}