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

Regulation of NF-κB signaling by the A20 deubiquitinase

The NF-κB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-κB is achieved by K63-linked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the IκB kinase (IKK). Ubiquitination is a highly dynamic process and is balanced by deubiquitinases that cleave polyubiquitin chains and terminate downstream signaling events. The A20 deubiquitinase is a critical negative regulator of NF-κB and inflammation, since A20-deficient mice develop uncontrolled and spontaneous multi-organ inflammation. Furthermore, specific polymorphisms in the A20 genomic locus predispose humans to autoimmune disease. Recent studies also indicate that A20 is an important tumor suppressor that is inactivated in B-cell lymphomas. Therefore, targeting A20 may form the basis of novel therapies for autoimmune disease and lymphomas

Outfoxing FoxO transcription factors: HTLV-1 Tax oncoprotein inactivates FoxO4 via the ubiquitin-proteasome pathway

Evaluation of: Oteiza A, Mechti N. The human T-cell leukemia virus type 1 oncoprotein tax controls forkhead box O4 activity through degradation by the proteasome. J. Virol. 85(13), 6480-6491 (2011). This study examines downstream signaling events of PI3K/AKT in the context of human T cell leukemia virus type 1 (HTLV-1) infection. The authors have demonstrated that the HTLV-1 Tax oncoprotein triggers the ubiquitination and proteasomal degradation of the FoxO4 transcription factor. Phosphorylation by AKT is requisite for Tax-induced FoxO4 degradation since mutation of the AKT phosphorylation sites abrogates FoxO4 degradation. Furthermore, Tax enhances the interaction between FoxO4 and the E3 ubiquitin ligase MDM2 which presumably leads to FoxO4 ubiquitination. Consistently, knockdown of MDM2 with a shRNA plasmid attenuates FoxO4 ubiquitination, revealing an important role for MDM2 in Tax-induced FoxO4 ubiquitination. Finally, Tax represses FoxO4 transcriptional activity in a dose-dependent manner. Taken together, the findings by Oteiza et al. suggest that Tax inactivates the tumor suppressor FoxO4 downstream of PI3K/AKT, which may play a role in HTLV-1-induced oncogenesis

Inhibition of NF-κB Signaling by A20 Through Disruption of Ubiquitin Enzyme Complexes

A20 negatively regulates inflammation by inhibiting the nuclear factor κB (NF-κB) transcription factor in the tumor necrosis factor receptor (TNFR) and Toll-like receptor (TLR) pathways. A20 contains deubiquitinase and E3 ligase domains and thus has been proposed to function as a ubiquitin-editing enzyme downstream of TNFR1 by inactivating ubiquitinated RIP1. However, it remains unclear how A20 terminates NF-κB signaling downstream of TLRs. We have shown that A20 inhibited the E3 ligase activities of TRAF6, TRAF2, and cIAP1 by antagonizing interactions with the E2 ubiquitin conjugating enzymes Ubc13 and UbcH5c. A20, together with the regulatory molecule TAX1BP1, interacted with Ubc13 and UbcH5c and triggered their ubiquitination and proteasome-dependent degradation. These findings suggest a mechanism of A20 action in the inhibition of inflammatory signaling pathways