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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.
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.
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.
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