TACI induces cIAP1-mediated ubiquitination of NIK by TRAF2 and TANK to limit non-canonical NF-κB signaling

Abstract

B-cell-activating factor of the TNF family (BAFF) is a critical factor for B-cell survival and maturation through non-canonical nuclear factor κB (NF-κB) pathway, a NF-κB inducing kinase (NIK)-dependent pathway for the processing of NF-κB2 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-κB2 activity is largely unknown. In this study, we showed that constitutive activation of TACI signaling suppressed BAFF-R–mediated NF-κB2 p100 processing with the up-regulation of cellular inhibitors of apoptosis 1 (cIAP1) and TNF receptor associated factor (TRAF)-associated NF-κB 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-κB2 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-κB signaling.

Keywords::

• BAFF-R
• NF-κB2 p100
• NIK
• TACI
• TANK

Acknowledgements

This work was supported by Dokkyo Medical University, Investigator-Initiated Research Grant (No. 2008-01-10). We thank Drs Hiroyasu Nakano and Adrian T. Ting for the valuable experimental support and discussion, Ms Keiko Kakuda and Ayano Kobayashi for the excellent technical assistance, and Ms Yoshie Nitta for secretarial assistance.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.