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

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.