The TRIF-RIPK1-Caspase-8 signalling in the regulation of TLR4-driven gene expression

Chengyang Zhang; Yang Zhou; Shuangtong Xi; Danlin Han; Ziyu Wang; Jingwen Zhu; Yizhe Cai; Haifeng Zhang; Ge Jin; Yang Mi

doi:10.1111/imm.13795

The TRIF-RIPK1-Caspase-8 signalling in the regulation of TLR4-driven gene expression

Immunology. 2024 Apr 15. doi: 10.1111/imm.13795. Online ahead of print.

Authors

Chengyang Zhang¹, Yang Zhou¹, Shuangtong Xi¹, Danlin Han¹, Ziyu Wang¹, Jingwen Zhu¹, Yizhe Cai¹, Haifeng Zhang¹, Ge Jin¹, Yang Mi¹

Affiliation

¹ Department of Biochemistry and molecular biology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China.

PMID: 38618995
DOI: 10.1111/imm.13795

Abstract

The inflammatory response is tightly regulated to eliminate invading pathogens and avoid excessive production of inflammatory mediators and tissue damage. Caspase-8 is a cysteine protease that is involved in programmed cell death. Here we show the TRIF-RIPK1-Caspase-8 is required for LPS-induced CYLD degradation in macrophages. TRIF functions in the upstream of RIPK1. The homotypic interaction motif of TRIF and the death domain of RIPK1 are essential for Caspase-8 activation. Caspase-8 cleaves CYLD and the D235A mutant is resistant to the protease activity of Caspase-8. TRIF and RIPK1 serve as substrates of Capase-8 in vitro. cFLIP interacts with Caspase-8 to modulate its protease activity on CYLD and cell death. Deficiency in TRIF, Caspase-8 or CYLD can lead to a decrease or increase in the expression of genes encoding inflammatory cytokines. Together, the TRIF-Caspase-8 and CYLD play opposite roles in the regulation of TLR4 signalling.

Keywords: CYLD; Caspase‐8; TLR4; TRIF; inflammatory cytokines; macrophage.