ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability

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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-08-19
DOI
https://doi.org/10.1073/pnas.2512154122
Citations
2
Primary Topic
Immune Response and Inflammation
Type
article
Field-Weighted Citation Impact
1.59

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article

ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability

Judy Lieberman, Huiqing Yu, Shenglin Mei, Wanyan Deng et al.
2 citations
Proceedings of the National Academy of Sciences
Immune Response and Inflammation
1.59
article

ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability

Judy Lieberman, Huiqing Yu, Shenglin Mei, Wanyan Deng, Yang Bai, Zengzhang Zheng, Rui Min, Zeyu Wu, Fan Deng, Xing Liu, Chao Zhang, Youdong Pan, Kang He, Jingxia Zhao, Haibo Liu
article en
2 citations

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.

Proceedings of the National Academy of SciencesVol. 122(34)
Brigham and Women's Hospital (US), Boston Children's Hospital (US), Shanghai Academy of Social Sciences (CN), Harvard University (US), Capital Medical University (CN), Employee Benefit Research Institute (US), Virginia–Maryland College of Veterinary Medicine (US), Institute of Cancer Research (CA), Shanghai East Hospital (CN), Beijing Hospital of Traditional Chinese Medicine (CN), Shanghai Academy of Environmental Sciences (CN), Institute of Infection and Immunity (CA), University of Chinese Academy of Sciences (CN), Chongqing Medical University (CN)
National Natural Science Foundation of China, Chinese Academy of Sciences, China Postdoctoral Science Foundation, Chinese Academy of Sciences, Shanghai Branch, National Postdoctoral Program for Innovative Talents, National Key Research and Development Program of China
Openalex Percentile: Top 15%
Immune Response and Inflammation
1.59
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