Background
The enzymes of the ubiquitylation pathway play a pivotal role in a number of cellular processes including the regulated and targeted proteasome-dependent degradation of substrate proteins. Three classes of enzymes are involved in the process of ubiquitylation; activating enzymes (E1s), conjugating enzymes (E2s) and protein ligases (E3s). Baculoviral IAP repeat containing protein 2 (BIRC2) is a member of the E3 protein ligase family and cloning of the human gene was first described by Rothe et al. (1995). BIRC2 is a RING finger domain ubiquitin E3 ligase that has been shown to ubiquitylate TRAF2 in TNF stimulated Jurkat cell lines (Li et al. 2002). Increased expression of HTRA2 induced by p53 results in the cleavage of BIRC2 and activation of apoptosis (Jin et al, 2003). BIRC2 has been shown to form part of a cytokine receptor signalling complex which also includes, Tnf Receptor-Associated Protein 2 (TRAF2), TRAF3, Ube2N, BIRC1, Inhibitor of Kappa Kappa gamma (IKKγ) and Mitogen Activated Protein Kinase Kinase Kinase 1 (MAP3K1). Activation of the kinases in this complex and translocation of the complex from the membrane to the cytosol was dependent upon TRAF3 degradation by BIRC1/BIRC2 (Matsuzawa et al, 2008). A20 can inhibit BIRC2, TRAF6 and TRAF2 E3 ligase activity in the NFƙbeta inflammatory signalling pathway by preventing its interaction with Ube2N and Ube2D3. (Shembade et al, 2010). In macrophages from BIRC2 null mice cytokine and chemokine production is reduced. Activation of NFƙbeta and Mapk induced by ubiquitylated RipK2 is reduced due to the lack of BIRC2. BIRC2 null mice also showed resistance to peritonitis induction and it is thought that BIRC2 is a key regulator of the Nucleotide-binding Oligomerization Domain receptor (NOD) innate immune response (Bertrand et al, 2009). More recently BIRC2 has been identified as an onocogene and expression has been found to be increased in squamous cell carcinoma of the cervix (Choschzick et al, 2012).
References
Bertrand MJM, Doiron K, Labbe K, Korneluk R G, Barker P A, Saleh M. (2009) Cellular inhibitors of apoptosis cIAP1 and cIAP2 are required for innate immunity signaling by the pattern recognition receptors NOD1 and NOD2. Immunity 30, 789-801.
Choschzick M, Tabibzada AM, Gieseking F, Woelber L, Jaenicke F, Sauter G, Simon R. (2012) BIRC2 amplification in squamous cell carcinomas of the uterine cervix. Virchows Arch 461, 123-8.
Jin S, Kalkum M, Overholtzer M, Stoffel A, Chait BT, Levine AJ. (2003) CIAP1 and the serine protease HTRA2 are involved in a novel p53-dependent apoptosis pathway in mammals. Genes Dev 17, 359-367.