RBCK1 Negatively Regulates Tumor Necrosis Factor- and Interleukin-1-triggered NF-κB Activation by Targeting TAB2/3 for Degradation

• Published in: The Journal of biological chemistry 2007-06, Vol.282 (23), p.16776
• Main Authors: Yang Tian, Yan Zhang, Bo Zhong, Yan-Yi Wang, Fei-Ci Diao, Rui-Peng Wang, Min Zhang, Dan-Ying Chen, Zhong-He Zhai, Hong-Bing Shu
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M701913200

Inflammation is a homeostatic mechanism that limits the effects of infectious agents. Tumor necrosis factor (TNF) and interleukin (IL)-1 are two cytokines that induce inflammation through activation of the transcription factor NF-κB. Various studies have suggested that two homologous and structurally related adapter proteins TAB2 and TAB3 play redundant roles in TNF- and IL-1-mediated NF-κB activation pathways. Both TAB2 and TAB3 contain CUE, coiled-coil, and nuclear protein localization 4 zinc finger (NZF) domains. The NZF domains of TAB2/3 are critical for TAB2/3 to bind to Lys 63 -linked polyubiquitin chains of other adaptor proteins, such as receptor-interacting protein and TRAF6, which are two signaling proteins essential for TNF- and IL-1-induced NF-κB activation, respectively. In a search for proteins containing NZF domains conserved with those of TAB2/3, we identified RBCK1, which has been shown to act as an E3 ubiquitin ligase in iron metabolism. Overexpression of RBCK1 negatively regulates TAB2/3-mediated and TNF- and IL-1-induced NF-κB activation, whereas knockdown of RBCK1 by RNA interference potentiates TNF- and IL-1-induced NF-κB activation. RBCK1 physically interacts with TAB2/3 and facilitates degradation of TAB2/3 through a proteasome-dependent process. Taken together, our findings suggest that RBCK1 is involved in negative regulation of inflammatory signaling triggered by TNF and IL-1 through targeting TAB2/3 for degradation.