TACI induces cIAP1-mediated ubiquitination of NIK by TRAF2 and TANK to limit non-canonical NF-kappaB signaling.
B-cell-activating factor of the TNF family (BAFF) is a critical factor for B-cell survival and maturation through non-canonical nuclear factor kappaB (NF-kappaB) pathway, a NF-kappaB inducing kinase (NIK)-dependent pathway for the processing of NF-kappaB2 p100 to generate p52. While BAFF acts primarily through BAFF receptor (BAFF-R), the transmembrane activator and CAML interactor (TACI), the other receptor for BAFF, is thought to serve as a negative regulator for B-cell responses. However, how TACI regulates NF-kappaB2 activity is largely unknown. In this study, we showed that constitutive activation of TACI signaling suppressed BAFF-R-mediated NF-kappaB2 p100 processing with the up-regulation of cellular inhibitors of apoptosis 1 (cIAP1) and TNF receptor associated factor (TRAF)-associated NF-kappaB activator (TANK). The ubiquitination of NIK by cIAP1 was inhibited by the expression of TRAF2 with physical binding to cIAP1. TANK deficiency by small interfering RNA (siRNA) impaired TACI-dependent inhibition of NF-kappaB2 p100 processing. TANK also inhibited TRAF2-mediated cIAP1 inactivation. Moreover, the recruitment of TRAF2 to TACI induced the ubiquitination of NIK. Taken together, the regulation of NIK by TACI through the interaction of TANK/TRAF2/cIAP1 plays a pivotal role in the suppression of non-canonical NF-kappaB signaling.
Kanno
Yumiko
Y
Department of Immunology, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
Sakurai
Daisuke
D
Hase
Hidenori
H
Kojima
Hidefumi
H
Kobata
Tetsuji
T
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D053303:Transmembrane Activator and CAML Interactor Protein / Q000378:metabolism*; D054875:Ubiquitination; D000097782:NF-kappaB-Inducing Kinase
D048868:Adaptor Proteins, Signal Transducing; D053265:B-Cell Activation Factor Receptor; D051034:Inhibitor of Apoptosis Proteins; D008156:Luciferases; D016328:NF-kappa B; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047992:TNF Receptor-Associated Factor 2; D053303:Transmembrane Activator and CAML Interactor Protein; D000097782:NF-kappaB-Inducing Kinase; C484406:TANK protein, human; C108467:TNFRSF13B protein, human; C435926:TNFRSF13C protein, human