Journal of Experimental Medicine, volume 222, issue 3

CCDC134 controls TLR biogenesis through the ER chaperone Gp96

Léa Bernaleau 1
Michaela Drobek 1
Fenja Blank 2
Philipp Walch 1
Maeva Delacrétaz 1
Ales Drobek 1
Marta Monguió-Tortajada 1
Petr Broz 1
Olivia Majer 2
Manuele Rebsamen 1
Show full list: 10 authors
Publication typeJournal Article
Publication date2024-12-10
scimago Q1
SJR6.838
CiteScore26.6
Impact factor12.6
ISSN00221007, 15409538
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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