RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-κB activation by targeting TAB2/3 for degradation

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-kappa B. 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-kappa B 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-kappa B 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-kappa B activation, whereas knockdown of RBCK1 by RNA interference potentiates TNF- and IL-1-induced NF-kappa B 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.