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sGRP78 enhances selective autophagy of monomeric TLR4 to regulate myeloid cell death

Zhenghao Wu1,2,3, Zhuoshuo Xu1, Xiaoqi Zhou1

  • 1Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.

Cell Death & Disease
|July 7, 2022
PubMed

Insights

Soluble glucose regulated protein 78 (sGRP78) clears endotoxins by promoting Toll-like receptor 4 (TLR4) degradation. This process involves autophagy, apoptosis, and ferroptosis, resolving inflammation.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Medicine

Background:

  • Soluble glucose regulated protein 78 (sGRP78) is implicated in resolving inflammation.
  • Previous work showed sGRP78 induces Toll-like receptor 4 (TLR4) endocytosis, impairing TLR4 signaling.

Purpose of the Study:

  • To investigate the mechanisms by which sGRP78 influences TLR4 behavior and trafficking in myeloid cells.
  • To elucidate the role of sGRP78 in endotoxin clearance and immune regulation.

Main Methods:

  • Investigated sGRP78 effects on LPS endocytosis and TLR4 trafficking in myeloid cells.
  • Analyzed TLR4 complex formation with p62-LC3 and degradation pathways.
  • Assessed the impact of autophagy-dependent TLR4 degradation on myeloid cell apoptosis and ferroptosis.

Main Results:

  • sGRP78 promotes LPS endocytosis involving monomeric TLR4.
  • Internalized monomeric TLR4 forms complexes with p62-LC3 and degrades in autolysosomes.
  • sGRP78-enhanced autophagy-dependent TLR4 degradation induces apoptosis and ferroptosis in myeloid cells.

Conclusions:

  • sGRP78-mediated TLR4 degradation is a novel mechanism for endotoxin clearance.
  • This process links innate immunity with autophagy, apoptosis, and ferroptosis for inflammation resolution.
  • Identified a shared resolution-associated molecular pattern (RAMP)-sGRP78 pathway.

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