| First Author | Pujari R | Year | 2015 |
| Journal | PLoS Pathog | Volume | 11 |
| Issue | 3 | Pages | e1004721 |
| PubMed ID | 25774694 | Mgi Jnum | J:245506 |
| Mgi Id | MGI:5915557 | Doi | 10.1371/journal.ppat.1004721 |
| Citation | Pujari R, et al. (2015) Human T-cell leukemia virus type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the NF-kappaB inhibitor A20 and constitutive NF-kappaB signaling. PLoS Pathog 11(3):e1004721 |
| abstractText | Persistent activation of NF-kappaB 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-kappaB 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-kappaB activation. Finally, Tax failed to inactivate the NF-kappaB 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-kappaB negative regulators, and maintain persistent NF-kappaB activation in HTLV-1 infected cells. |
