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

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. © 2015 pujari et al.