2. Academic Validation
  3. sGRP78 enhances selective autophagy of monomeric TLR4 to regulate myeloid cell death

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

  • Cell Death Dis. 2022 Jul 7;13(7):587. doi: 10.1038/s41419-022-05048-5.
Zhenghao Wu  # 1 2 3,  Zhuoshuo Xu  # 1,  Xiaoqi Zhou 1,  Heli Li 1,  Liang Zhao 1,  Yibing Lv 1,  Yanyan Guo 1,  Guanxin Shen 1,  Yong He 4,  Ping Lei 5
Affiliations

Affiliations

  • 1 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China.
  • 2 Department of Nuclear Medicine and PET Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
  • 3 Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
  • 4 Department of Nuclear Medicine and PET Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China. heyong@znhospital.cn.
  • 5 Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China. adaleip@hust.edu.cn.
  • # Contributed equally.
PMID: 35798718 DOI: 10.1038/s41419-022-05048-5
Abstract

Soluble glucose regulated protein 78 (sGRP78) has long been suggested as a mediator resolution of inflammation. We previously reported that sGRP78 induced the rapid endocytosis of TLR4 with defective TLR4 signaling. To elucidate the underlying mechanisms, in this study, we investigated how sGRP78 influenced the behavior and trafficking of TLR4 in myeloid cells. It was found that sGRP78 promoted LPS endocytosis with monomeric TLR4. This internalized monomeric TLR4 formed complexes with p62-LC3, and was degraded in autolysosomes. Furthermore, the sGRP78-enhanced autophagy-dependent TLR4 degradation caused Apoptosis and Ferroptosis in myeloid cells, contributing to the sGRP78-mediated resolution of inflammation. These reports establish innovative mechanisms for endotoxin clearance and immune regulation by TLR4 degradation, linking innate immunity with multiple ancient processes, including Autophagy, Apoptosis, and Ferroptosis, together through a shared resolution-associated molecular pattern (RAMP)-sGRP78.

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