HTLV-1 Tax Stabilizes MCL-1 via TRAF6-Dependent K63-Linked Polyubiquitination to Promote Cell Survival and Transformation

The human t-cell leukemia virus type 1 (htlv-1) tax protein hijacks the host ubiquitin machinery to activate iκb kinases (ikks) and nf-κb and promote cell survival; however,the key ubiquitinated factors downstream of tax involved in cell transformation are unknown. using mass spectrometry,we undertook an unbiased proteome-wide quantitative survey of cellular proteins modified by ubiquitin in the presence of tax or a tax mutant impaired in ikk activation. tax induced the ubiquitination of 22 cellular proteins,including the anti-apoptotic bcl-2 family member mcl-1,in an ikk-dependent manner. tax was found to promote the nondegradative lysine 63 (k63)-linked polyubiquitination of mcl-1 that was dependent on the e3 ubiquitin ligase traf6 and the ikk complex. tax interacted with and activated traf6,and triggered its mitochondrial localization,where it conjugated four carboxyl-terminal lysine residues of mcl-1 with k63-linked polyubiquitin chains,which stabilized and protected mcl-1 from genotoxic stress-induced degradation. traf6 and mcl-1 played essential roles in the survival of htlv-1 transformed cells and the immortalization of primary t cells by htlv-1. therefore,k63-linked polyubiquitination represents a novel regulatory mechanism controlling mcl-1 stability that has been usurped by a viral oncogene to precipitate cell survival and transformation. © 2014 choi,harhaj.