PDLIM2-mediated termination of transcription factor NF-kappaB activation by intranuclear sequestration and degradation of the p65 subunit.
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.
Tanaka
Takashi
T
Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
Grusby
Michael J
MJ
Kaisho
Tsuneyasu
T
D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D016328:NF-kappa B; C502929:PDLIM2 protein, human; C508508:Pdlim2 protein, mouse; D021122:Protein Subunits; D051193:Toll-Like Receptors; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex