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.
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http://dx.doi.org/10.1371/journal.ppat.1004721 | DOI Listing |
Nutrients
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Cooperative Major of Advanced Health Science, Tokyo University of Agriculture and Technology, 2-24-16 Naka, Koganei 184-8588, Tokyo, Japan.
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December 2024
School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, China.
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January 2025
Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, CA, USA.
DNA damage in cells induces the expression of inflammatory genes. However, the mechanism by which cells initiate an innate immune response in the presence of DNA lesions blocking transcription remains unknown. Here we find that genotoxic stresses lead to an acute activation of the transcription factor NF-κB through two distinct pathways, each triggered by different types of DNA lesions and coordinated by either ataxia-telangiectasia mutated (ATM) or IRAK1 kinases.
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Institute for Experimental Pediatric Hematology and Oncology, Goethe University Frankfurt, Frankfurt am Main, Germany.
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December 2024
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, PR China; Ningbo Institute of Marine Medicine, Peking University, Beijing 100191, PR China. Electronic address:
Prenylated indole diketopiperazines represent a diverse array of alkaloids with complex chemical scaffolds and with a wide range of biological activities. Aiming to discover bioactive metabolites with structural novelty, genomic annotation in association with the MS/MS-based molecular networking demonstrated a deep-sea derived fungus Aspergillus puulaauensis F77 containing a profile of diketopiperazines. Targeted separation of the cultured fungus led to the isolation of 19 undescribed austamide-type diketopiperazines namely versicoines A-S.
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