ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Yang Bai
Chao Zhang
Hao Liu
Fan Deng
State Key Laboratory of Immune Response and Immunotherapy, State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences
Zeyu Wu
State Key Laboratory of Immune Response and Immunotherapy, State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences
Wanyan Deng
State Key Laboratory of Immune Response and Immunotherapy, State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences
Zengzhang Zheng
State Key Laboratory of Immune Response and Immunotherapy, State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences
Rui Min
State Key Laboratory of Immune Response and Immunotherapy, State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences
Shenglin Mei
Fralin Biomedical Research Institute (FBRI), Virginia Tech FBRI Cancer Research Center
He Kang
State Key Laboratory of Immune Response and Immunotherapy, State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences
Huiqing Yu
State Key Laboratory of Immune Response and Immunotherapy, State Key Laboratory of RNA Innovation, Science and Engineering, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences
Youdong Pan
Judy Lieberman
Jingxia Zhao
Beijing Institute of Traditional Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University
Xing Liu