Abstract
TNF induced nuclear factor kappa B (NF-κB) is one of the central signaling pathways that plays a critical role in carcinogenesis and inflammatory diseases. Post-translational modification through ubiquitin plays important role in the regulation of this pathway. In the current study, we investigated the role of TRIM8, member of RING family ubiquitin ligase in regulation of NF-κB pathway. We observed that TRIM8 positively regulates TNF induced NF-κB pathway. Different domains of TRIM8 showed discrete functions at the different steps in regulation of TNF induced NF-κB pathway. Ubiquitin ligase activity of TRIM8 is essential for regulation of NF-κB activation in both cytoplasm as well as nucleus. TRIM8 negates PIAS3 mediated negative repression of NF-κB at p65 by inducing translocation of PIAS3 from nucleus to cytoplasm as well as its turnover. TNF induces translocation of TRIM8 from nucleus to cytoplasm, which positively regulates NF-κB. The cytoplasmic translocation of TRIM8 is essential for TNF induced NF-κB but not for p65 mediated NF-κB regulation. TRIM8 also enhanced the clonogenic and migration ability of cells by modulating NF-κB. The further study will help to understand the role of TRIM8 in inflammation and cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line, Tumor
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Cell Movement / genetics
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Cell Nucleus / metabolism
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Cytoplasm / metabolism
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Enzyme Activation
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Gene Silencing
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Humans
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I-kappa B Kinase / metabolism*
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MCF-7 Cells
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Molecular Chaperones / metabolism
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Protein Inhibitors of Activated STAT / metabolism
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Protein Interaction Domains and Motifs
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Protein Transport
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Signal Transduction / drug effects*
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Carrier Proteins
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Molecular Chaperones
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Nerve Tissue Proteins
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PIAS3 protein, human
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Protein Inhibitors of Activated STAT
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TRIM8 protein, human
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Tumor Necrosis Factor-alpha
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I-kappa B Kinase
Grants and funding
This study was supported by the Program Support to Indian Institute of Advanced Research (IIAR) sponsored by Department of Biotechnology (DBT), Govt. of India. Dhanendra Tomar received Senior Research Fellowship from Council of Scientific and Industrial Research (CSIR), Govt. of India. Lakshmi Sripada received Junior Research Fellowship from University Grant Commission (UGC), Govt. of India. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.