Kelch-like Protein 21 (KLHL21) Targets I?B Kinase-? to Regulate Nuclear Factor ?-Light Chain Enhancer of Activated B Cells (NF-?B) Signaling Negatively.

ABSTRACT: Activation of IKK? is the key step in canonical activation of NF-?B signaling. Extensive work has provided insight into the mechanisms underlying IKK? activation through the identification of context-specific regulators. However, the molecular processes responsible for its negative regulation are not completely understood. Here, we identified KLHL21, a member of the Kelch-like gene family, as a novel negative regulator of IKK?. The expression of KLHL21 was rapidly down-regulated in macrophages upon treatment with proinflammatory stimuli. Overexpression of KLHL21 inhibited the activation of IKK? and degradation of I?B?, whereas KLHL21 depletion via siRNA showed the opposite results. Coimmunoprecipitation assays revealed that KLHL21 specifically bound to the kinase domain of IKK? via its Kelch domains and that this interaction was gradually attenuated upon TNF? treatment. Furthermore, KLHL21 did not disrupt the interaction between IKK? and TAK1, TRAF2, or I?B?. Also, KLHL21 did not require its E3 ubiquitin ligase activity for IKK? inhibition. Our findings suggest that KLHL21 may exert its inhibitory function by binding to the kinase domain and sequestering the region from potential IKK? inducers. Taken together, our data clearly demonstrate that KLHL21 negatively regulates TNF?-activated NF-?B signaling via targeting IKK?, providing new insight into the mechanisms underlying NF-?B regulation in cells.

SUBMITTER: Mei ZZ 

PROVIDER: S-EPMC5000066 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature