HTLV-1 tax stabilizes MCL-1 via TRAF6-dependent K63-linked polyubiquitination to promote cell survival and transformation.

Young Bong Choi,Edward William Harhaj,Susan R Ross

doi:10.1371/journal.ppat.1004458

Young Bong Choi, Edward William Harhaj + Show 1 more

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https://doi.org/10.1371/journal.ppat.1004458

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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.

Highlights

Human T-cell leukemia virus 1 (HTLV-1) infects approximately 20 million people worldwide and is the etiological agent of adult T-cell leukemia (ATL), an aggressive CD4+CD25+ malignancy that occurs in a small percentage of infected individuals after a long latent period [1]
Our findings have uncovered a novel mode of regulation of MCL-1 stability that has been hijacked by the HTLV-1 Tax oncoprotein to promote cell transformation
A ubiquitin proteomics screen revealed that Tax modulated the ubiquitination of 136 cellular proteins, of which 22 of these candidates required IkB kinases (IKKs) for Tax-induced ubiquitination

Summary

Introduction

Human T-cell leukemia virus 1 (HTLV-1) infects approximately 20 million people worldwide and is the etiological agent of adult T-cell leukemia (ATL), an aggressive CD4+CD25+ malignancy that occurs in a small percentage of infected individuals after a long latent period [1]. HTLV-1 Tax is a key regulatory protein essential for viral gene expression by recruiting CREB/ATF transcription factors to the viral long terminal repeats (LTRs) [2]. Tax plays a central role in cell transformation by HTLV-1 and is sufficient to immortalize primary human T lymphocytes [3]. Transgenic mice expressing Tax in the T-cell compartment develop leukemia and lymphoma with clinical and pathological features resembling ATL [4]. Survival and immortalization of T cells by inactivating tumor suppressors, promoting cell cycle progression and activating anti-apoptotic pathways [5]. One of the principal cellular pathways targeted by Tax and essential for Taxmediated transformation is NF-kB [6]

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