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Regulation of Cell Death and Immunity by XIAP
Philipp J Jost1,2,3, Domagoj Vucic4
1Medical Department III, School of Medicine, Technical University of Munich, 81675 Munich, Germany.
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.
Insights
X-chromosome-linked inhibitor of apoptosis protein (XIAP) regulates cell death and inflammation. XIAP
Area of Science:
- Cell Biology
- Immunology
- Molecular Biology
Background:
- X-chromosome-linked inhibitor of apoptosis protein (XIAP) is a key regulator of cell survival and apoptosis.
- XIAP also plays a critical role in inflammatory signaling pathways.
Purpose of the Study:
- To elucidate the multifaceted roles of XIAP in cell death and inflammation.
- To highlight XIAP as a potential therapeutic target.
Main Methods:
- The study reviews existing literature on XIAP's functions.
- It discusses XIAP's interactions with caspases, RIPK1, and NOD2 signaling components.
Main Results:
- XIAP inhibits apoptosis triggered by intrinsic and extrinsic pathways.
- XIAP prevents TNF-mediated cell death by regulating RIPK1 ubiquitylation.
- XIAP mediates NOD2 signaling, promoting inflammatory responses via RIPK2 ubiquitination, NF-κB, and MAPK activation.
Conclusions:
- XIAP is a crucial regulator of both programmed cell death and inflammatory responses.
- Its involvement in multiple pathways makes XIAP a promising drug target for cancer and inflammatory diseases.