| Human T-lymphotropic virus 1 (HTLV-I) was the first human retrovirus discovered to be linked to a disease. It infects more than 15 million individuals throughout the world, and causes several serious diseases such as tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM) and adult T-cell leukemia/lymphoma (ATL). Current studies showed that Tax, a regulatory protein of HTLV-1, activates the IKK-NF-κB signaling pathway of host cells, which is required for the pathogenicity of HTLV-1. But the underlying molecular mechanism remains unclear. Here, by using a cell-free system, we showed that ubiquitin-conjugating enzymes (E2s) UbcH2, UbcH5c or UbcH7 are required for Tax-dependent IKK activation. Furthermore, we found that Tax is an ubiquitin ligase (E3), which, together with those E2s, catalyzes the assembly of free mixed-linkage polyubiquitin chains, and these polyubiquitin chains activate IKK directly. Our results elucidated the detailed molecular mechanism for IKK-NF-κB activation by Tax, and may shed light on therapeutics for treatment of HTLV-1 infection.Aspirin and salicylate are widely used anti-inflammatory and analgesic drugs. The effectiveness of these drugs has been widely ascribed to their activity in inhibiting cyclooxygenases COX-1/2, but that cannot explain all the effects of aspirin and salicylate. By using an in vitro system, we found that aspirin and salicylate inhibit ubiquitination. Further studies showed that aspirin and salicylate are pan-inhibitors of the ubiquitin-conjugating enzymes (E2s), which inhibit all the E2s tested with variable degrees. Aspirin and salicylate inhibit ubiquitination resulting in blockage of the sequential activation of transforming growth factor (TGF)-β-activated kinase (TAK1), inhibitor of κB (IκB) kinase (IKK) and NF-κB, therefore exhibiting their anti-inflammatory effect. Our results elucidated a new mechanism of aspirin and salicylate, which may provide theoretical base for clinical application of aspirin. |
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