RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-kappaB 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-kappaB. 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-kappaB 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-kappaB 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-kappaB activation, whereas knockdown of RBCK1 by RNA interference potentiates TNF- and IL-1-induced NF-kappaB 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.
Tian
Yang
Y
College of Life Sciences, Peking University, Beijing 100871, China.
Zhang
Yan
Y
Zhong
Bo
B
Wang
Yan-Yi
YY
Diao
Fei-Ci
FC
Wang
Rui-Peng
RP
Zhang
Min
M
Chen
Dan-Ying
DY
Zhai
Zhong-He
ZH
Shu
Hong-Bing
HB
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D006801:Humans; D006868:Hydrolysis; D007375:Interleukin-1 / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C410585:TAB2 protein, human; C481053:TAB3 protein, human; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C504507:RBCK1 protein, human; D044767:Ubiquitin-Protein Ligases