ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability

• 成果类型: Article
• 署名作者: Bai, Yang; Zhang, Chao; Liu, Hao; Deng, Fan; Wu, Zeyu; Deng, Wanyan; Zheng, Zengzhang; Min, Rui; Mei, Shenglin; Kang, He; Yu, Huiqing; Pan, Youdong; Lieberman, Judy; Zhao, Jingxia; Liu, Xing
• 署名单位: Chinese Academy of Sciences; Shanghai Institute of Immunity and Infection, CAS; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chongqing Medical University; Tongji University; Virginia Polytechnic Institute & State University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Brigham & Women's Hospital; Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); Harvard University; Harvard Medical School; Capital Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14740
• DOI: 10.1073/pnas.2512154122
• 发表日期: 2025-08-26
• 关键词: toll-like receptors; secretory protein; complex; prat4a; localization; TRAFFICKING; RECOGNITION; chaperones; unc93b1; adapter

摘要

Toll-like receptor 4 (TLR4), a pattern-recognition receptor located on the plasma membrane, senses extracellular danger signals to initiate inflammatory immune responses. It is initially synthesized in the endoplasmic reticulum (ER), undergoes N-linked glycosylation, and is subsequently transported to the Golgi before ultimately reaching the plasma membrane. However, the mechanisms underlying the processing and maturation of TLR4 in the ER remain elusive. Through whole genome-wide CRISPR screening, CCDC134 was identified as a critical and essential factor for TLR4-dependent inflammatory response. Localization of CCDC134 in the ER lumen rather than its exosome-mediated secretion is required for its role in TLR4 signaling. Loss of CCDC134 results in the retention of TLR4 in the ER for subsequent ER-associated degradation, and thus blockade of TLR4 maturation and plasma membrane trafficking. Defects in TLR4 processing and maturation in the ER in CCDC134-depleted cells are caused by aberrant hyperglycosylation and destabilization of glycoprotein 96 (gp96), a key chaperone of TLR4. These results suggest that CCDC134 controls gp96 glycosylation to facilitate TLR4 maturation in the ER.