SIP蛋白调节p65核转位的作用机制

Mechanism Involved in Cytoplasmic Sequestration of p65 by SIP

核因子κB(nuclear factor-κB,NF-κB)参与转录调控许多与细胞生长、凋亡、肿瘤形成和转移、胚胎发育及炎症反应相关的基因.它的二聚体与抑制蛋白结合,如抑制蛋白κB(IκBα,β或γ),而被滞留在细胞质中处于失活状态.然而NF-κB是否还有其它的抑制因子目前还不清楚.本研究结果表明,SIP(steroid receptor coactivator,SRC,SRC-interacting protein)是NF-κB家族的一个新抑制因子,它通过PEST结构域与NF-κB家族的p65蛋白相互作用.当细胞处于静息状态时,SIP将p65蛋白隔离于细胞质中;当有刺激因子TNFα或IL-1作用时,SIP与p65解离继而使p65进入细胞核启动下游靶基因转录激活.该研究为进一步认识NF-κB介导基因转录调控机制和相关疾病的发生发展提供了重要的理论依据.

Nuclear factor-κB（NF-κB） is a pleiotropic transcription factor regulating over 200 genes involved in cell growth,apoptosis,tumorigenesis and metastasis,embryonic development and inflammatory effects.Under most circumstances,NF-κB lies dormant in the cytoplasm of unstimulated cells,kept there by an inhibitory protein termed IκB.Many signals inactivate the inhibitor IκB,thereby allowing NF-κB to enter nuclei and rapidly induce sets of defense-related genes.However,whether there are other inhibitory proteins of NF-κB is currently not clear.We report here that SIP（steroid receptor coactivator,SRC,SRC-interacting protein,SIP） interacts with p65 through its PEST domain in the cytoplasm.Furthermore,fluorescence confocal microscopy and luciferase reporter assays indicated that extracellular stimuli such as the addition of TNFα or IL-1 induced SIP to dissociate from p65 in the cytoplasm and led to subsequent nuclear translocation of p65 proteins and gene coactivation.Both gain-of-function and loss-of-function experiments indicate that SIP functions to sequester p65 in the cytoplasm and buffer the availability of the NF-κB transcription factors.Our experiments indicate that SIP is a novel inhibitory protein for p65,adding another layer in the regulatory network of the NF-κB pathway.