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


HTLV-1 infection is etiologically linked to the development of the neuroinflammatory disorder HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL), an aggressive CD4+CD25+ malignancy. The HTLV-1 regulatory protein Tax constitutively activates the IκB kinases (IKKs) and NF-κB to promote cell survival, proliferation and transformation. However, the precise mechanisms by which Tax and IKK regulate cell survival are largely unknown. Here, we found that Tax interacts with and activates the host ubiquitin ligase TRAF6, and promotes a redistribution of TRAF6 to the mitochondria. TRAF6 conjugates the anti-apoptotic BCL-2 family member MCL-1 with lysine 63 (K63)-linked polyubiquitin chains that antagonize MCL-1 interaction with the 20S proteasome, thereby protecting MCL-1 from degradation elicited by chemotherapeutic drugs. TRAF6 and MCL-1 both played pivotal roles in the survival of ATL cells and the immortalization of primary T cells by HTLV-1. Overall, our study has identified a novel TRAF6/MCL-1 axis that has been subverted by the HTLV-1 Tax protein to maintain the survival of HTLV-1 infected T cells.


Vyšlo v časopise: HTLV-1 Tax Stabilizes MCL-1 via TRAF6-Dependent K63-Linked Polyubiquitination to Promote Cell Survival and Transformation. PLoS Pathog 10(10): e32767. doi:10.1371/journal.ppat.1004458
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.ppat.1004458

Souhrn

HTLV-1 infection is etiologically linked to the development of the neuroinflammatory disorder HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia (ATL), an aggressive CD4+CD25+ malignancy. The HTLV-1 regulatory protein Tax constitutively activates the IκB kinases (IKKs) and NF-κB to promote cell survival, proliferation and transformation. However, the precise mechanisms by which Tax and IKK regulate cell survival are largely unknown. Here, we found that Tax interacts with and activates the host ubiquitin ligase TRAF6, and promotes a redistribution of TRAF6 to the mitochondria. TRAF6 conjugates the anti-apoptotic BCL-2 family member MCL-1 with lysine 63 (K63)-linked polyubiquitin chains that antagonize MCL-1 interaction with the 20S proteasome, thereby protecting MCL-1 from degradation elicited by chemotherapeutic drugs. TRAF6 and MCL-1 both played pivotal roles in the survival of ATL cells and the immortalization of primary T cells by HTLV-1. Overall, our study has identified a novel TRAF6/MCL-1 axis that has been subverted by the HTLV-1 Tax protein to maintain the survival of HTLV-1 infected T cells.


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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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