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CCDC134 controls TLR biogenesis through the ER chaperone Gp96

Léa Bernaleau1, Michaela Drobek1, Fenja Blank2

  • 1Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.

The Journal of Experimental Medicine
|December 10, 2024
PubMed

Insights

CCDC134 is crucial for Toll-like receptor (TLR) function. It regulates the Gp96 chaperone, ensuring proper TLR folding, maturation, and immune response activation.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Toll-like receptors (TLRs) initiate immune responses but require strict regulation to prevent autoimmune diseases.
  • Multilevel regulatory mechanisms control TLRs to balance host defense and pathological inflammation.

Purpose of the Study:

  • To identify novel regulators of Toll-like receptor (TLR) signaling pathways.
  • To elucidate the role of CCDC134 in immune responses mediated by TLRs.

Main Methods:

  • Conducted a loss-of-function genetic screen using a reporter cell line sensitive to TLR7 activation.
  • Investigated the interaction between CCDC134 and Gp96 (HSP90B1/Grp94) in the endoplasmic reticulum.
  • Assessed the impact of CCDC134 deficiency on TLR folding, maturation, trafficking, and downstream signaling.

Main Results:

  • CCDC134 was identified as an essential factor for TLR responses.
  • CCDC134 deficiency impaired endolysosomal TLR-induced activation of NF-κB, MAPK, and IRF5.
  • CCDC134 regulates Gp96 stability, preventing its degradation and ensuring proper TLR biogenesis and inflammatory cytokine production.

Conclusions:

  • CCDC134 is a critical regulator of Gp96, a chaperone essential for Toll-like receptor (TLR) biogenesis.
  • CCDC134 controls TLR folding, maturation, and trafficking, thereby modulating immune responses.
  • CCDC134 deficiency leads to impaired inflammatory signaling and cytokine production.

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