Tanaka Takashi, Grusby Michael J, Kaisho Tsuneyasu
Laboratory for Host Defense, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
Nat Immunol. 2007 Jun;8(6):584-91. doi: 10.1038/ni1464. Epub 2007 Apr 29.
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.
在天然免疫系统中，转录因子NF-κB的激活受到严格调控，以防止过度的炎症反应。然而，NF-κB激活是如何终止的，目前尚未完全清楚。在此，我们报告PDLIM2负向调控NF-κB活性，作为一种靶向NF-κB p65亚基的核泛素E3连接酶发挥作用。PDLIM2与p65结合并促进p65多聚泛素化。此外，PDLIM2将p65靶向到离散的核内区室，在那里多聚泛素化的p65被蛋白酶体降解。PDLIM2缺陷导致核内p65含量增加、p65泛素化缺陷以及对天然刺激产生的促炎细胞因子产量增加。我们的研究结果描绘了一条PDLIM2通过核内隔离和随后的降解来终止NF-κB激活的途径。
