tailieunhanh - Báo cáo khoa học: The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid

The truncated C-terminal portion of Bid (tBid) is an important intermedi-ate in ligand-induced apoptosis. tBid has been shown to be sensitive to pro-teasomal inhibitors and downregulated by activation of the epidermal growth factor (EGF) pathway. Here, we provide evidence that tBid is a substrate of the ubiquitin ligase Itch, which can specifically interact with and ubiquitinate tBid, but not intact Bid. | ỊFEBS Journal The ubiquitin ligase Itch mediates the antiapoptotic activity of epidermal growth factor by promoting the ubiquitylation and degradation of the truncated C-terminal portion of Bid Bilal A. Azakir Guillaume Desrochers and Annie Angers Departement de sciences biologiques Universite de Montreal Quebec Canada Keywords apoptosis Bid c-Jun N-terminalkinase epidermal growth factor HECT domain ubiquitin Correspondence A. Angers Departement de sciences biologiques Universite de Montreal . Box 6128 station Centre-Ville Montreal Quebec H3C 3J7 Canada Fax 1 514 343 2293 Tel 1 514 343 7012 E-mail Received 2 November 2009 revised 21 December 2009 accepted 24 December 2009 doi The truncated C-terminal portion of Bid tBid is an important intermediate in ligand-induced apoptosis. tBid has been shown to be sensitive to pro-teasomal inhibitors and downregulated by activation of the epidermal growth factor EGF pathway. Here we provide evidence that tBid is a substrate of the ubiquitin ligase Itch which can specifically interact with and ubiquitinate tBid but not intact Bid. Consistently overexpression of Itch increases cell survival and inhibits caspase 3 activity whereas downregulation of Itch by RNA interference has the opposite effect increasing cell death and apoptosis. Treatment with EGF increases Itch phosphorylation and activity and Itch expression is important for the ability of EGF to increase cell survival after tumour necrosis factor-related apoptosis-inducing ligand treatment. Our findings identify Itch as a key molecule between EGF signalling and resistance to apoptosis through downregulation of tBid providing further details on how EGF receptor and proteasome inhibitors can contribute to the induction of apoptosis and the treatment of cancer. Structural digital abstract MINT-7542954 ITCH uniprotkb Q96J02 physically interacts MI 0915 with tBid uniprotkb P70444 by anti tag coimmunoprecipitation MI