RIPK1 in the inflammatory response and sepsis: Recent advances, drug discovery and beyond

Abstract

Cytokine storms are an important mechanism of sepsis. TNF-α is an important cytokine. As a regulator of TNF superfamily receptors, RIPK1 not only serves as the basis of the scaffold structure in complex I to promote the activation of the NF-κB and MAPK pathways but also represents an important protein in complex II to promote programmed cell death. Ubiquitination of RIPK1 is an important regulatory function that determines the activation of cellular inflammatory pathways or the activation of death pathways. In this paper, we introduce the regulation of RIPK1, RIPK1 PANoptosome's role in Inflammatory and sepsis, and perspectives.

Keywords: PANoptosis; RIPK1; cytokine storm; inflammatory response; sepsis.

Figure 1

Structure and modification sites of RIPK1. RIPK1 comprises the N-terminal kinase domain, the C-terminal death domain that mediates death signaling, the bridging intermediate domain, and the RIP homotypic interaction motif (RHIM). Phosphorylation sites have two opposite effects: S161 and S166 have a pro-death effect and are phosphorylated after TNF-αstimulate, while S25, T189, S321, S335, and S336 have a pro-survival effect and are phosphorylated by IKK, MK2, and TAK. Ubiquitination sites can be linked by different Ub chains: K115 can be linked by K63 and M1 chain, K376 linked by K11, K63, and M1 chain, K612 linked by M1 chain, while K584 remains unknown. Pink circle with P indicates phosphorylation sites, a yellow circle with Ub indicates ubiquitination sites, green dots indicate K11 ub chain, brown dots indicates K63 ub chain, purple dots indicate M1 ub chain, grey indicates unknown ub chain.

Figure 2

Regulation of RIPK1 and downstream effect. After stimulated by TNF-α, TRADD, TRAF2, RIPK1 and cIAPs would recruit to the intracellular terminus of TNFR1, then RIPK1 is ubiquitinated to form complex I, activating NF-κB and MAPK pathway. When RIPK1 has been deubiquitinated, the cell death pathway would be activated, triggering necroptosis, apoptosis and pyroptosis.