Human T-Cell leukemia virus type 1 (HTLV- 1) tax requires CADM1/TSLC1 for inactivation of the NF-ÎoB inhibitor A20 and constitutive NF-ÎoB signaling

Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1) recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells. PLOS Pathogens | DOI:10.1371/journal.ppat.1004721 March 16, 2015 1 / 27 OPEN ACCESS Citation: Pujari R, Hunte R, Thomas R, van der Weyden L, Rauch D, Ratner L, et al. (2015) Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Requires CADM1/TSLC1 for Inactivation of the NF-κB Inhibitor A20 and Constitutive NF-κB Signaling. PLoS Pathog 11(3): e1004721. doi:10.1371/journal.ppat.1004721 Editor: Susan R Ross, University of Pennsylvania School of Medicine, UNITED STATES Received: July 30, 2014 Accepted: January 31, 2015 Published: March 16, 2015 Copyright: © 2015 Pujari et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: These studies were supported in part by UM SJG 2012-39 from the Stanley J. Glaser Foundation and IRG-98-277-13 from the American Cancer Society to NS, and PHS grants: CA94056, CA10073, CA63417 to LR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist.