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

Department of Microbiology and Immunology, Viral Oncology Program, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, Florida, United States of America.

Published: March 2015

AI Article Synopsis

  • Persistent activation of NF-κB by the Tax protein from HTLV-1 is crucial for the development of adult T-cell leukemia (ATL) and associated neurological disorders.
  • Tax interacts with various cellular components, notably CADM1, to activate the IKK complex and inhibit the negative regulator A20, which impacts NF-κB signaling.
  • The study highlights the importance of CADM1 as a scaffold that supports the formation of a complex necessary for Tax to maximize NF-κB activation in infected cells.

Article Abstract

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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361615PMC
http://dx.doi.org/10.1371/journal.ppat.1004721DOI Listing

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