hCINAP negatively regulates NF-κB signaling by recruiting the phosphatase PP1 to deactivate IKK complex

Tight regulation of nuclear factor-kB(NF-kB)signaling is essential to maintain homeostasis in immune system in response to various stimuli,which hasbeen studied extensivelyand deeply.However,the molecularmechanisms responsible for its negative regulation are not completely understood.Here we demonstrate that human coilin-interacting nuclear ATPase protein(hCINAP)is a novel negative regulator in NF-kB signaling by deactivating IkB kinase(IKK)complex.In response to TNF stimulation,hCINAP dynamically associates with IKKa and IKKb and inhibits IKK phosphorylation.Notably,hCINAP directly interacts with the catalytic subunits of protein phosphatase 1(PP1)and mediates the formation of IKK–hCINAP–PP1 complex,serving as an adaptor protein that recruits PP1 to dephosphorylate IKK.Furthermore,decreased levels of hCINAP are observed in several inflammatory diseases with NF-kB hyperactivity.Our study suggests a novel mechanism underlying deactivation of IKK and provides new insight into the negative regulation of NF-kB signaling.

Non-SMC condensin Ⅰ complex subunit D2 and non-SMC condensin Ⅱ complex subunit D3 induces inflammation via the IKK/NF-κB pathway in ulcerative colitis

BACKGROUND Ulcerative colitis(UC)is a chronic,nonspecific intestinal inflammatory disease with undefined pathogenesis.Non-SMC condensin I complex subunit D2(NCAPD2)and non-SMC condensin II complex subunit D3(NCAPD3)play pivotal roles in chromosome assembly and segregation during both mitosis and meiosis.To date,there has been no relevant report about the functional role of NCAPD2 and NCAPD3 in UC.AIM To determine the level of NCAPD2/3 in intestinal mucosa and explore the mechanisms of NCAPD2/3 in UC.METHODS Levels of NCAPD2/3 in intestinal tissue were detected in 30 UC patients and 30 healthy individuals with in situ hybridization(ISH).In vitro,NCM60 cells were divided into the NC group,model group,si-NCAPD2 group,si-NCAPD3 group and si-NCAPD2+si-NCAPD3 group.Inflammatory cytokines were measured by ELISA,IKK and NF-κB were evaluated by western blot,and IKK nucleation and NF-κB volume were analyzed by immunofluorescence assay.RESULTS Compared with expression in healthy individuals,NCAPD2 and NCAPD3 expression in intestinal tissue was significantly upregulated(P<0.001)in UC patients.Compared with levels in the model group,IL-1β,IL-6 and TNF-αin the si-NCAPD2,si-NCAPD3 and si-NCAPD2+si-NCAPD3 groups were significantly downregulated(P<0.01).IKK and NF-κB protein expression in the si-NCAPD2,si-NCAPD3 and si-NCAPD2+si-NCAPD3 groups was significantly decreased(P<0.01).Moreover,IKK nucleation and NF-κB volume were suppressed upon si-NCAPD2,si-NCAPD3 and si-NCAPD2+si-NCAPD3 transfection.CONCLUSION NCAPD2/3 is highly expressed in the intestinal mucosa of patients with active UC.Overexpression of NCAPD2/3 promotes the release of pro-inflammatory cytokines by modulating the IKK/NF-κB signaling pathway.

IKK激酶的NF-κB非相关性功能研究进展

IKK复合物由IKKα、IKKβ和IKKγ组成,是NF-κB通路中的重要分子,主要调控NF-κB通路的活化。近年的研究发现,IKK复合物还存在许多NF-κB非相关性的功能,主要涉及肿瘤发生、应激反应、转录调控、免疫功能及细胞周期调控等方面。IKK复合物的NF-κB非相关性的功能研究集中于IKKα和IKKβ亚基,并且存在激酶活性依赖和非依赖2种作用方式。对于该功能的深入探讨,对全面理解IKK分子的生理病理功能十分重要,并且为IKK分子的研究提出了一个新的方向。

NF-κB研究进展及其与炎症的关系

文中详细综述了NF-κB信号通路的组成、激活途径及其与人类炎症性疾病的相关性,并对其未来发展进行了展望。

NF-κB在炎症相关癌症中的双重作用

目前,癌症是全球第二大死亡人数最多的疾病。炎症反应是一个复杂的生理学过程,涉及到生物体中细胞以及分子层面的广泛变化。在组织修复,伤口愈合以及抵御外来病原体入侵的过程中,有序的炎症反应是机体免疫系统产生的正常防御反应,保证机体的健康。但当这种急性炎症持续较长时间且得不到有效控制时,就易发展成慢性炎症,从而促进许多疾病的发生,包括风湿性关节炎,心血管疾病,阿尔茨海默症和癌症等。越来越多的证据表明,炎症反应失调在癌症中起到关键作用,长期使用非甾体类抗炎药(Non-steroidal anti-inflammatory drugs,NSAIDs)可以降低多种癌症的发病率。文章重点综述了核因子-κB(Nuclear factor-kappa B,NF-κB)在炎癌中的复杂作用,包括NF-κB对炎症反应具有的正向和负向调节作用,以及它如何影响肿瘤的发生和发展。深度解析NF-κB在炎-癌转化中的作用对于现代肿瘤生物学来说是一个重要挑战。