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PMID: 21981915 Published · ppublish English Journal Article Review

RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts.

Molecular cell ·Vol. 44 ·No. 1 ·2011-10-07 ·Pages 9-16

Green DR, Oberst A, Dillon CP, Weinlich R, Salvesen GS

Abstract

Caspase-8, FADD, and FLIP orchestrate apoptosis in response to death receptor ligation. Mysteriously however, these proteins are also required for normal embryonic development and immune cell proliferation, an observation that has led to their implication in several nonapoptotic processes. While many scenarios have been proposed, recent genetic and biochemical evidence points to unregulated signaling by the receptor-interacting protein kinases-1 (RIPK1) and RIPK3 as the lethal defect in caspase-8-, FADD-, and FLIP-deficient animals and tissues. The RIPKs are known killers, being responsible for a nonapoptotic form of cell death with features similar to necrosis. However, the mechanism by which caspase-8, FADD, and FLIP prevent runaway RIPK activation is unknown, and the signals that trigger these events during development and immune cell activation remain at large. In this review, we will lay out the evidence as it now stands, reinterpreting earlier observations in light of new clues and considering where the investigation might lead.

MeSH Terms
Animals Apoptosis CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism Caspase 8/metabolism Fas-Associated Death Domain Protein/metabolism Gene Expression Regulation, Enzymologic Humans Mice Mice, Knockout Necrosis Receptor-Interacting Protein Serine-Threonine Kinases/metabolism
Chemicals
CASP8 and FADD-Like Apoptosis Regulating Protein CFLAR protein, human Cflar protein, mouse FADD protein, human Fadd protein, mouse Fas-Associated Death Domain Protein RIPK1 protein, human RIPK3 protein, human Receptor-Interacting Protein Serine-Threonine Kinases Ripk1 protein, mouse Ripk3 protein, mouse Caspase 8
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Green Douglas R
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. douglas.green@stjude.org
Oberst Andrew
Dillon Christopher P
Weinlich Ricardo
Salvesen Guy S
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2011.09.003
Email
douglas.green@stjude.org
Published
2011-10-07
Pages
9-16
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3192321
Subset
IM
Grants
NIGMS NIH HHS · R37 GM052735-21 · United States
NIAID NIH HHS · R01 AI047891 · United States
NIAID NIH HHS · R01 AI047891-14 · United States
NIGMS NIH HHS · R37 GM052735 · United States
NIAID NIH HHS · R01 AI044828-13 · United States
NIAID NIH HHS · R01 AI044828 · United States
External Links
PubMed source DOI: 10.1016/j.molcel.2011.09.003 PMC Full Text View journal details
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