CCDC134 controls TLR biogenesis through the ER chaperone Gp96.

IF 12.6 1区 医学 Q1 IMMUNOLOGY
Journal of Experimental Medicine Pub Date : 2025-03-03 Epub Date: 2024-12-10 DOI:10.1084/jem.20240825
Léa Bernaleau, Michaela Drobek, Fenja Blank, Philipp Walch, Maeva Delacrétaz, Ales Drobek, Marta Monguió-Tortajada, Petr Broz, Olivia Majer, Manuele Rebsamen
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引用次数: 0

Abstract

Toll-like receptors (TLRs) are central to initiate immune responses against invading pathogens. To ensure host defense while avoiding aberrant activation leading to pathogenic inflammation and autoimmune diseases, TLRs are tightly controlled by multilevel regulatory mechanisms. Through a loss-of-function genetic screen in a reporter cell line engineered to undergo cell death upon TLR7-induced IRF5 activation, we identified here CCDC134 as an essential factor for TLR responses. CCDC134 deficiency impaired endolysosomal TLR-induced NF-κB, MAPK, and IRF5 activation, as well as downstream production of proinflammatory cytokines and type I interferons. We further demonstrated that CCDC134 is an endoplasmic reticulum (ER)-resident interactor of Gp96 (HSP90B1/Grp94), an ER chaperone essential for folding and trafficking of plasma membrane and endolysosomal TLRs. CCDC134 controlled Gp96 stability as its loss led to Gp96 hyperglycosylation and ER-associated protein degradation (ERAD)-mediated clearance. Accordingly, CCDC134 deficiency impaired the folding, maturation, and trafficking of TLRs, resulting in blunted inflammatory responses upon stimulation. Altogether, this study reveals CCDC134 as a central regulator of the chaperone Gp96, thereby controlling TLR biogenesis and responses.

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来源期刊
CiteScore
26.60
自引率
1.30%
发文量
189
审稿时长
3-8 weeks
期刊介绍: Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field. Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions. Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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