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PDLIM2-mediated termination of transcription factor NF-kappaB activation by intranuclear sequestration and degradation of the p65 subunit.

Nature immunology | Jun 21, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17468759

Activation of transcription factor NF-kappaB in the innate immune system is tightly regulated to prevent excessive inflammatory responses. How NF-kappaB activation is terminated, however, is not fully understood. Here we report that PDLIM2 negatively regulated NF-kappaB activity, acting as a nuclear ubiquitin E3 ligase targeting the p65 subunit of NF-kappaB. PDLIM2 bound to p65 and promoted p65 polyubiquitination. In addition, PDLIM2 targeted p65 to discrete intranuclear compartments where polyubiquitinated p65 was degraded by the proteasome. PDLIM2 deficiency resulted in larger amounts of nuclear p65, defective p65 ubiquitination and augmented production of proinflammatory cytokines in response to innate stimuli. Our findings delineate a pathway by which PDLIM2 terminates NF-kappaB activation through intranuclear sequestration and subsequent degradation.

Pubmed ID: 17468759 RIS Download

Mesh terms: Active Transport, Cell Nucleus | Adaptor Proteins, Signal Transducing | Animals | Cell Nucleus | Cells, Cultured | Humans | LIM Domain Proteins | Mice | Mice, Knockout | Microfilament Proteins | NF-kappa B | Proteasome Endopeptidase Complex | Protein Binding | Protein Subunits | Signal Transduction | Toll-Like Receptors | Ubiquitin | Ubiquitin-Protein Ligases

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