2. Academic Validation
  3. ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability

ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability

  • Proc Natl Acad Sci U S A. 2025 Aug 26;122(34):e2512154122. doi: 10.1073/pnas.2512154122.
Yang Bai # 1,  Chao Zhang # 1 2,  Hao Liu # 1,  Fan Deng 1 2,  Zeyu Wu 1 2,  Wanyan Deng 1 3,  Zengzhang Zheng 1 4,  Rui Min 1 2,  Shenglin Mei 5 6,  He Kang 1,  Huiqing Yu 1,  Youdong Pan 7,  Judy Lieberman 8 9,  Jingxia Zhao 10,  Xing Liu 1 11
Affiliations

Affiliations

  • 1 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, Shanghai 200031, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Key Laboratory of Molecular Biology on Infectious Diseases, Chongqing Medical University, Chongqing 400042, China.
  • 4 State Key Laboratory of Cardiovascular Diseases and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai 200120, China.
  • 5 Fralin Biomedical Research Institute (FBRI), Virginia Tech FBRI Cancer Research Center, Washington, DC 20012.
  • 6 Department of Biomedical Sciences and Pathobiology, College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061.
  • 7 Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
  • 8 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115.
  • 9 Department of Pediatrics, Harvard Medical School, Boston, MA 02115.
  • 10 Beijing Institute of Traditional Chinese Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China.
  • 11 Shanghai Academy of Natural Sciences (SANS), Shanghai 200031, China.
  • # Contributed equally.
PMID: 40828012 DOI: 10.1073/pnas.2512154122
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.

Keywords

CCDC134; TLR4; gp96; inflammation.

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