Several E3 ligases are involved in TNF-α signaling to initiate an immediate and effective host response to infection or injury. Among them are anti-apoptotic regulators BIRC2 and BIRC3, also known as inhibitor of apoptosis proteins (cIAP1/2). BIRC2/3 were found to constitutively associate with TRAF2 and via TRAF2 they were recruited to the TNFR1 signaling complex (Samuel T et al. 2006; Bertrand et al, 2008; Varfolomeev E et al, 2008). BIRC2/3 can directly ubiquitinate RIPK1 within the TNFR1 receptor complex allowing it to bind to the TAB2:TAK1 complex, a process reversed by the deubiquitinase CYLD and A20 (Bertrand et al, 2008; Varfolomeev et al, 2008; Moquin DM et al. 2013; Shembade N et al. 2010; Wertz IE et al. 2004). In conjunction with the ubiquitin conjugating enzyme (E2) enzyme UbcH5a, BIRC2/3 was shown to mediate polymerization of both K63-linked and linear Met1-linked chains on RIPK1 (Varfolomeev E et al, 2008; Bertrand et al, 2008; Blackwell K et al. 2013). TRAF2 promotes BIRC-mediated linear and K63-linked ubiquitination of RIP1 (Blackwell K et al. 2013). K11-linked polyubiquitination of RIPK1 may also depend on BIRC2 and BIRC3 (Dynek JN et al. 2010).
Zapata, JM, Lober, T, Welsh, K, Reed, JC, Togo, SH, Samuel, T
Wang, Y, Wu, H, Zheng, C, Cheng, G, Kabaleeswaran, V
ubiquitin-protein transferase activity of TNF-α:TNFR1:TRADD:RIP1:TRAF2:BIRC2/3 [plasma membrane]
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