title: HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation.
abstract: 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.
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Young Bong
authors.initials: YB
authors.lastname: Choi
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Edward William
authors.initials: EW
authors.lastname: Harhaj
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004249:DNA Damage; D016356:Gene Products, tax / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000302:isolation & purification*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*
chemical_list: D016356:Gene Products, tax; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; C514970:tax protein, Human T-lymphotrophic virus 1; D025821:Polyubiquitin; D008239:Lysine