| First Author | Mei ZZ | Year | 2016 |
| Journal | J Biol Chem | Volume | 291 |
| Issue | 35 | Pages | 18176-89 |
| PubMed ID | 27387502 | Mgi Jnum | J:236157 |
| Mgi Id | MGI:5805307 | Doi | 10.1074/jbc.M116.715854 |
| Citation | Mei ZZ, et al. (2016) Kelch-like Protein 21 (KLHL21) Targets IkappaB Kinase-beta to Regulate Nuclear Factor kappa-Light Chain Enhancer of Activated B Cells (NF-kappaB) Signaling Negatively. J Biol Chem 291(35):18176-89 |
| abstractText | Activation of IKKbeta is the key step in canonical activation of NF-kappaB signaling. Extensive work has provided insight into the mechanisms underlying IKKbeta 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 IKKbeta. The expression of KLHL21 was rapidly down-regulated in macrophages upon treatment with proinflammatory stimuli. Overexpression of KLHL21 inhibited the activation of IKKbeta and degradation of IkappaBalpha, whereas KLHL21 depletion via siRNA showed the opposite results. Coimmunoprecipitation assays revealed that KLHL21 specifically bound to the kinase domain of IKKbeta via its Kelch domains and that this interaction was gradually attenuated upon TNFalpha treatment. Furthermore, KLHL21 did not disrupt the interaction between IKKbeta and TAK1, TRAF2, or IkappaBalpha. Also, KLHL21 did not require its E3 ubiquitin ligase activity for IKKbeta inhibition. Our findings suggest that KLHL21 may exert its inhibitory function by binding to the kinase domain and sequestering the region from potential IKKbeta inducers. Taken together, our data clearly demonstrate that KLHL21 negatively regulates TNFalpha-activated NF-kappaB signaling via targeting IKKbeta, providing new insight into the mechanisms underlying NF-kappaB regulation in cells. |
