BIRC3

BIRC3 Background

Baculoviral inhibitors of apoptosis repeat-containing protein 3 (BIRC3), also called cellular inhibitors of apoptosis 2 (cIAP2), is a protein in humans that is encoded by BIRC3 gene ^[1][2]. The cIAP2 protein contains three BIR domains (BIR1-BIR3), a CARD (caspase-recruitment) domain and a RING (really interesting new gene) zinc-finger domain ^[3]. The RING domain of cIAP2 possesses E3 ubiquitin ligase activity, which directly regulates auto- or trans-ubiquitination and protein degradation ^[4][5]. The BIR1 domains of cIAP2 play a role in tumor necrosis factor (TNF) receptor-associated factor (TRAF) interactions and ubiquitination reactions ^[5][6]. Conze DB et al. demonstrated that cIAP1 ubiquitination of cIAP2 leads to low protein levels of cIAP2 in normal conditions by validating cIAP1 E3 ligase function with the cIAP1-null mouse ^[7]. Increased BIRC3, in combination with BIRC2, acts simultaneously as a positive factor for NF-kappa B signaling ^[8][9], but also as a molecular brake that provides modulatory control over the JNK signaling axis ^[10]. In the absence of both cIAP1 and cIAP2, TNF alpha-mediated NF- kappa B signaling is dramatically attenuated in many cells, including normal primary cells as well as transformed cancer cells ^[11]. Consequently, the dual loss of cIAP1 and cIAP2 greatly sensitizes cells to TNF alpha-mediated apoptosis. A recent report also suggests that cIAP1 and cIAP2 promote cancer cell survival by ubiquitinating RIP1, leading to constitutive RIP1 and NF-kappa B activity ^[12]. High expression of XIAP or cIAP2 is associated with shorter overall survival, and lower complete response rates for AML ^[13].

[1] Liston P, Roy N, et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes [J]. Nature. February 1996, 379 (6563): 349-53.
[2] Rothe M, Pan MG, et al. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins [J]. Cell. February 1996, 83 (7): 1243-52.
[3] Hinds MG, Norton RS, et al. Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat [J]. Nat Struct Biol 1999, 6: 648-651.
[4] Yang Y, Fang S, Jensen JP, et al. Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli [J]. Science 2000, 288: 874-877.
[5] Vaux DL, Silke J. IAPs, RINGs and ubiquitylation [J]. Nat Rev Mol Cell Biol 2005, 6: 287-297.
[6] Samuel T, Welsh K, et al. Distinct BIR domains of cIAP1 mediate binding to and ubiquitination of tumor necrosis factor receptor-associated factor 2 and second mitochondrial activator of caspases [J]. J Biol Chem 2006, 281: 1080-1090.
[7] Conze DB, Albert L, et al. Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo [J]. Mol Cell Biol 2005, 25: 3348-3356.
[8] Mahoney DJ, Cheung HH, et al. Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation.[J] Proc Natl Acad Sci U S A, 2008, 105:11778-11783.
[9] Varfolomeev E, Goncharov T, et al. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation [J]. J Biol Chem 2008, 283:24295-24299.
[10] B. M. Tan, N. W. Zammit, et al. Baculoviral inhibitors of apoptosis repeat containing (BIRC) proteins fine-tune TNF-induced nuclear factor κB and c-Jun N-terminal kinase signaling in mouse pancreatic beta cells [J]. Diabetologia volume 2013, 56, pages520-532 (2013).
[11] Varfolomeev E, Wayson SM, et al. The inhibitor of apoptosis protein fusion c-IAP2.MALT1 stimulates NF-kappaB activation independently of TRAF1 AND TRAF2 [J]. J Biol Chem 2006, 281: 29022- 29029.
[12] Bertrand MJ, Milutinovic S, et al. cIAP1 and cIAP2 facilitate cancer cell survival by functioning as E3 ligases that promote RIP1 ubiquitination [J]. Mol Cell 2008, 30: 689-700.
[13] Hess CJ, Berkhof J, et al. Activated intrinsic apoptosis pathway is a key related prognostic parameter in acute myeloid leukemia [J]. J Clin Oncol 2007, 25: 1209-1215.