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

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.

The expression of cell adhesion molecule 1 and its splicing variants in Sézary cells and cell lines from cutaneous T‐cell lymphoma

“…It has been postulated that CADM1 expression is induced by human T-cell leukemia virus 1 (HTLV-1)-encoded gene products such as Tax and HBZ in ATLL. 13,16 But this scenario cannot explain the fact that CADM1 is expressed by S ezary cells without HTLV-1 infection.…”

“…Our study indicates that the expression of CADM1 is not a simple activation marker, because CD3/CD28 stimulation of normal human lymphocytes induced CD25 and HLA‐DR expression, but did not induce CADM1. It has been postulated that CADM1 expression is induced by human T‐cell leukemia virus 1 (HTLV‐1)‐encoded gene products such as Tax and HBZ in ATLL . But this scenario cannot explain the fact that CADM1 is expressed by Sézary cells without HTLV‐1 infection.…”

NF-κB and MicroRNA Deregulation Mediated by HTLV-1 Tax and HBZ

“…CADM1 (also known as TSLC1, NECL-2, IGSF4, SynCAM1) acts as a tumor suppressor in a variety of human cancers [91,92] and has been proposed as a cell surface marker for ATLL [93]. Pujari et al suggest that Tax-1 may require CADM1 to inactivate negative regulators of NF-κB and maintain persistent NF-κB activation [94]. The same authors demonstrated that CADM1 is upregulated by Tax-1 and associates with Tax-1 in cellular complexes containing Ubc13, TAX1BP1, OPTN, and NEMO in membrane lipid raft microdomains [94,95].…”

PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma

“…In patients with ATLL , CADM1 expression in combination with CD7 downregulation closely correlates with clonal expansion of leukemic cells (14). Functionally, trans-homophilic interactions of CADM1 activates PI3K (15) and NF-kB (16), whereas trans-heterophilic CADM1 interaction triggers recruitment of the RAC1 GEF, TIAM1, to the CADM1cytoplasmic domain, leading to RAC1 activation and remodeling of actin-network and lamellipodia formation (11). Although RAC1 is known to be required for CADM1 function in ATLL, PAK kinases supporting CADM1-dependent stroma adhesion of ATLL cells have not been defined.…”