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ER-resident CCDC134 safeguards TLR4 maturation by maintaining gp96 stability.

Yang Bai1, Chao Zhang1,2, Hao Liu1

  • 1State 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.

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|August 19, 2025
PubMed
Summary

CCDC134 protein is essential for Toll-like receptor 4 (TLR4) maturation in the endoplasmic reticulum. It regulates TLR4 inflammatory responses by controlling glycoprotein 96 (gp96) glycosylation, preventing TLR4 degradation.

Keywords:
CCDC134TLR4gp96inflammation

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Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Toll-like receptor 4 (TLR4) initiates inflammatory responses upon sensing danger signals.
  • TLR4 maturation involves synthesis in the endoplasmic reticulum (ER), glycosylation, and transport to the plasma membrane.
  • Mechanisms of TLR4 processing and maturation within the ER are not fully understood.

Purpose of the Study:

  • To identify critical factors involved in Toll-like receptor 4 (TLR4) maturation and inflammatory signaling.
  • To elucidate the role of CCDC134 in the endoplasmic reticulum (ER) processing of TLR4.

Main Methods:

  • Whole genome-wide CRISPR screening was employed to identify essential factors for TLR4 signaling.
  • Cellular localization studies assessed the role of CCDC134 in the ER lumen versus secretion.
  • Analysis of TLR4 trafficking, degradation, and glycosylation of its chaperone, glycoprotein 96 (gp96), in CCDC134-depleted cells.

Main Results:

  • CCDC134 was identified as a critical factor for TLR4-dependent inflammatory responses.
  • CCDC134's function requires its localization within the ER lumen.
  • Loss of CCDC134 leads to ER retention and degradation of TLR4 due to aberrant gp96 glycosylation and destabilization.
  • CCDC134 is essential for proper TLR4 maturation and plasma membrane transport.

Conclusions:

  • CCDC134 controls glycoprotein 96 (gp96) glycosylation in the ER.
  • This regulation by CCDC134 facilitates Toll-like receptor 4 (TLR4) maturation and trafficking.
  • CCDC134 is a key regulator of TLR4 processing and subsequent inflammatory immune responses.