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

摘要: 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 promote cell survival; however, key ubiquitinated factors downstream of involved in transformation are unknown. Using mass spectrometry, we undertook an unbiased proteome-wide quantitative survey cellular proteins modified by presence or a mutant impaired IKK activation. induced ubiquitination 22 proteins, including anti-apoptotic BCL-2 family member MCL-1, IKK-dependent manner. was found nondegradative lysine 63 (K63)-linked polyubiquitination MCL-1 that dependent on E3 ligase TRAF6 complex. interacted with activated TRAF6, triggered its mitochondrial localization, where it conjugated four carboxyl-terminal residues K63-linked polyubiquitin chains, which stabilized protected from genotoxic stress-induced degradation. played essential roles survival HTLV-1 transformed cells immortalization primary T HTLV-1. Therefore, represents novel regulatory mechanism controlling stability has been usurped viral oncogene precipitate transformation.