RHIMdomain

RHIM domain

The RHIM domain, short for RIP homotypic interaction motif, is a small, conserved protein interaction module found in a subset of signaling proteins involved in innate immunity and regulated cell death. The motif mediates homotypic and heterotypic interactions and often promotes the assembly of higher-order, amyloid-like filaments that serve as scaffolds to propagate signaling events.

Proteins that bear RHIM motifs include RIPK1 and RIPK3, ZBP1 (also known as DAI), and the adaptor TRIF. In addition, various viral proteins encode RHIM-containing sequences that disrupt host signaling by sequestering RIPK1 and RIPK3, thereby inhibiting necroptosis. Notable examples include certain cytomegalovirus proteins that exploit RHIM interactions to blunt antiviral responses.

Function and signaling context: The RHIM domain contributes to necroptosis, a regulated form of necrotic cell death. Following death receptor engagement and in conditions where caspase-8 is inhibited, RIPK1 and RIPK3 interact through their RHIM motifs to form the necrosome. This complex activates RIPK3, which phosphorylates MLKL. Phosphorylated MLKL then oligomerizes and disrupts cellular membranes to execute necroptosis, contributing to inflammatory signaling and pathogen defense.

Regulation and significance: RHIM-mediated interactions are modulated by post-translational modifications and cellular context, including ubiquitination of RIPK1. Viral antagonists that target RHIM networks illustrate the evolutionary tug-of-war between host defense and pathogen evasion. Due to its central role in inflammation and cell death, the RHIM domain is a focus of ongoing research for therapeutic modulation of necroptosis.

See also: necroptosis, RIPK1, RIPK3, ZBP1, TRIF, MLKL.