Caspase-cleaved arrestin-2 and BID cooperatively facilitate cytochrome C release and cell death.

Kook S, Zhan X, Cleghorn WM, Benovic JL, Gurevich VV, Gurevich EV
Cell Death Differ. 2014 21 (1): 172-84

PMID: 24141717 · PMCID: PMC3857626 · DOI:10.1038/cdd.2013.143

Apoptosis is programmed cell death triggered by activation of death receptors or cellular stress. Activation of caspases is the hallmark of apoptosis. Arrestins are best known for their role in homologous desensitization of G protein-coupled receptors (GPCRs). Arrestins quench G protein activation by binding to activated phosphorylated GPCRs. Recently, arrestins have been shown to regulate multiple signalling pathways in G protein-independent manner via scaffolding signalling proteins. Here we demonstrate that arrestin-2 isoform is cleaved by caspases during apoptosis induced via death receptor activation or by DNA damage at evolutionarily conserved sites in the C-terminus. Caspase-generated arrestin-2-(1-380) fragment translocates to mitochondria increasing cytochrome C release, which is the key checkpoint in cell death. Cells lacking arrestin-2 are significantly more resistant to apoptosis. The expression of wild-type arrestin-2 or its cleavage product arrestin-2-(1-380), but not of its caspase-resistant mutant, restores cell sensitivity to apoptotic stimuli. Arrestin-2-(1-380) action depends on tBID: at physiological concentrations, arrestin-2-(1-380) directly binds tBID and doubles tBID-induced cytochrome C release from isolated mitochondria. Arrestin-2-(1-380) does not facilitate apoptosis in BID knockout cells, whereas its ability to increase caspase-3 activity and facilitate cytochrome C release is rescued when BID expression is restored. Thus, arrestin-2-(1-380) cooperates with another product of caspase activity, tBID, and their concerted action significantly contributes to cell death.

MeSH Terms (15)

Animals Apoptosis Arrestins BH3 Interacting Domain Death Agonist Protein Caspase 3 Caspases Cell Line Cytochromes c Etoposide Mice Mitochondria Protein Binding Protein Isoforms Recombinant Proteins Tumor Necrosis Factor-alpha

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