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 he host ulaiqui in machinery to activate [KB kinases (IKKs) and NF-KB and promote cell su val- however, the key ubiquitina ed factors downstream of Tax involved in cel transformation are unknown. transformation are Using mass spectrometry, we undertook an unbiased protearrie-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 an apop o ic family member MCL-1, in an KK-dependent manner. Tax was found to promote the nondegradative lysine 63 (K63)-linked polyubiqui !nation of IVICL-1 that was dependent on the E3 LlbiqLlitin ligase TRAF6 and the IKK complex. Tax interacted with and activated TRAF6, and triggered its to 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 re nduced degradation. TRAF6 and MCLplayed 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 polyubiqui Ina ion represents a novel regulatory mechanism controlling ped by a viral oncogene to precipitate cell survival and transformation.