Cellular inhibitor of apoptosis proteins (BIRC2, BIRC3 also known as cIAP1 and cIAP2) are E3 ubiquitin ligases that contribute to the cell survival by conjugating ubiquitin chains to components of cell death-activating platforms (such as ripoptosome, TNFR1- or toll like receptor 3 signaling complexes). BIRC2 or 3 can generate K11, K48- or K63-linked polyubiquitin chains depending on the cell content (Varfolomeev E et al, 2008; Bertrand MJM et al, 2008; Dynek JN et al. 2010). For instance, BIRC2/3-mediated K63-linked ubiquitination of RIPK1 enables activation of pro-survival NFkB signaling events downstream of TNFR1 complex, while cell level of free active RIPK1 can be controlled by targeting RIPK1 for proteasomal degradation via BIRC2/3-mediated K48-linked polyubiquitination (Varfolomeev E et al, 2008; Bertrand MJM et al. 2008; Tenev T et al. 2011; Darding M & Meier P 2012). Such BIRC2/3-mediated events prevent the formation of cell death signaling platforms. Following genotoxic stress, cytokine signaling-induced depletion of BIRCs, or Smac mimetics treatment, BIRC2, BIRC3, and XIAP levels rapidly decline and/or are inactivated (Bertrand MJM et al. 2008; Tenev T et al. 2011; Feoktistova M et al. 2011). BIRC2/3 antagonist are thought to induce self-mediated K48-linked ubiquitination followed by a proteasomal degradation. This allows accumulation of RIPK1 and formation of ripoptosome or other RIPK1-dependent death signaling platforms. In the absence of BIRCs the balance between caspase-dependent apoptosis and RIP-dependent necroptosis was found to depend on the levels of caspase-8, CFLAR (cFLIPL) and also FLIP(S) (Feoktistova M et al. 2011). CFLAR prevented apoptosis and necroptosis, whereas FLIPS inhibited apoptosis but promoted necroptosis (Feoktistova M et al. 2011; Dillon CP et al. 2012; Oberst A et al. 2001).
Zapata, JM, Lober, T, Welsh, K, Reed, JC, Togo, SH, Samuel, T
Langlais, C, Geserick, P, Kellert, B, Häcker, G, Cain, K, Feoktistova, M, Hupe, M, MacFarlane, M, Leverkus, M, Dimitrova, DP
Morris, SJ, Milutinovic, S, Gillard, JW, Durkin, J, Ho, WC, Dickson, KM, Boudreault, A, Barker, PA, Bertrand, MJ, Jaquith, JB
ubiquitin-protein transferase activity of BIRC2,3,4 [cytosol]
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