1. RBCK1 Negatively Regulates Tumor Necrosis Factor- and lnterleukin-1 -triggered NF-κB Activation by Targeting TAB2/3 for Degradation.
- Author
-
Yang Tian, Van Zhang, Bo Zhong, Yan-Yi Wang, Fei-Ci Diao, Rui-Peng Wang, Min Zhang, Dan-Ying Chen, Zhong-He Zhai, and Hong-Bing Shu
- Subjects
- *
PROTEINS , *TUMOR necrosis factors , *UBIQUITIN , *RNA , *INTERLEUKINS - Abstract
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 Lys63-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 TAB2I3 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. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF