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 re...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.展开更多
基金supported by the National Science Foundation of China(31170709,31470754)the Seeding Grant for Medicine and Life Sciences of Peking University(2014-MB-02)the Doctoral Fund of Ministry of Education of China(20130001130003).
文摘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.
