Regulation of Cell Death and Immunity by XIAP

Cold Spring Harb Perspect Biol. 2020 Aug 3;12(8):a036426. doi: 10.1101/cshperspect.a036426.

Abstract

X-chromosome-linked inhibitor of apoptosis protein (XIAP) controls cell survival in several regulated cell death pathways and coordinates a range of inflammatory signaling events. Initially identified as a caspase-binding protein, it was considered to be primarily involved in blocking apoptosis from both intrinsic as well as extrinsic triggers. However, XIAP also prevents TNF-mediated, receptor-interacting protein 3 (RIPK3)-dependent cell death, by controlling RIPK1 ubiquitylation and preventing inflammatory cell death. The identification of patients with germline mutations in XIAP (termed XLP-2 syndrome) pointed toward its role in inflammatory signaling. Indeed, XIAP also mediates nucleotide-binding oligomerization domain-containing 2 (NOD2) proinflammatory signaling by promoting RIPK2 ubiquitination within the NOD2 signaling complex leading to NF-κB and MAPK activation and production of inflammatory cytokines and chemokines. Overall, XIAP is a critical regulator of multiple cell death and inflammatory pathways making it an attractive drug target in tumors and inflammatory diseases.

Publication types

  • Review

MeSH terms

  • Animals
  • Apoptosis
  • Cell Death
  • Chemokines / metabolism
  • Cytokines / metabolism
  • Humans
  • Immune System
  • Inflammation
  • Inhibitor of Apoptosis Proteins / metabolism*
  • MAP Kinase Signaling System
  • Mutation
  • NF-kappa B p50 Subunit / metabolism
  • Nod Signaling Adaptor Proteins / metabolism
  • Nod2 Signaling Adaptor Protein / metabolism*
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Syndrome
  • X-Linked Inhibitor of Apoptosis Protein / metabolism*

Substances

  • Birc4 protein, mouse
  • Chemokines
  • Cytokines
  • Inhibitor of Apoptosis Proteins
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • NOD2 protein, human
  • Nod Signaling Adaptor Proteins
  • Nod2 Signaling Adaptor Protein
  • Nod2 protein, mouse
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Nfkb1 protein, mouse
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk3 protein, mouse