Reactome | BIRC2/3 (cIAP1/2) is autoubiquitinated

BIRC2/3 (cIAP1/2) is autoubiquitinated

Stable Identifier

R-HSA-5675470

Type

Reaction [omitted]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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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).

Literature References

PubMed ID	Title	Journal	Year
16282325	Distinct BIR domains of cIAP1 mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases Zapata, JM, Lober, T, Welsh, K, Reed, JC, Togo, SH, Samuel, T	J. Biol. Chem.	2006
21737330	cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms Langlais, C, Geserick, P, Kellert, B, Häcker, G, Cain, K, Feoktistova, M, Hupe, M, MacFarlane, M, Leverkus, M, Dimitrova, DP	Mol. Cell	2011
18570872	cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination Morris, SJ, Milutinovic, S, Gillard, JW, Durkin, J, Ho, WC, Dickson, KM, Boudreault, A, Barker, PA, Bertrand, MJ, Jaquith, JB	Mol. Cell	2008