CD27, a Member of the Tumor Necrosis Factor Receptor Superfamily, Activates NF-κB and Stress-activated Protein Kinase/c-Jun N-terminal Kinase via TRAF2, TRAF5, and NF-κB-inducing Kinase

Hisaya Akiba,Hiroyasu Nakano,Shigeyuki Nishinaka,Masahisa Shindo,Tetsuji Kobata,Machiko Atsuta,Chikao Morimoto,Carl F Ware,Nikolai L Malinin,David Wallach,Hideo Yagita,Ko Okumura

doi:10.1074/jbc.273.21.13353

Abstract

CD27 is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed on T, B, and NK cells. The signal via CD27 plays pivotal roles in T-T and T-B cell interactions. Here we demonstrate that overexpression of CD27 activates NF-kappaB and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK). Deletion analysis of the cytoplasmic domain of CD27 revealed that the C-terminal PIQEDYR motif was indispensable for both NF-kappaB and SAPK/JNK activation and was also required for the interaction with TNF receptor-associated factor (TRAF) 2 and TRAF5, both of which have been implicated in NF-kappaB activation by members of the TNF-R superfamily. Co-transfection of a dominant negative TRAF2 or TRAF5 blocked NF-kappaB and SAPK/JNK activation induced by CD27. Recently, a TRAF2-interacting kinase has been identified, termed NF-kappaB-inducing kinase (NIK). A kinase-inactive mutant NIK blocked CD27-, TRAF2-, and TRAF5-mediated NF-kappaB and SAPK/JNK activation. These results indicate that TRAF2 and TRAF5 are involved in NF-kappaB and SAPK/JNK activation by CD27, and NIK is a common downstream kinase of TRAF2 and TRAF5 for NF-kappaB and SAPK/JNK activation.

Highlights

CD27 is a member of the tumor necrosis factor receptor (TNF-R)1 superfamily and is expressed on T, B, and NK cells as a disulfide-linked homodimer [1]
These results indicated that CD27 interacts with TRAF2 and TRAF5, and the PIQEDYR motif in the cytoplasmic region is responsible for TNF receptor-associated factors (TRAFs) binding and NF-␬B activation
We demonstrated that CD27 associates with TRAF2 and TRAF5, and these TRAFs are implicated in NF-␬B and stress-activated protein kinase (SAPK)/Jun N-terminal kinase (JNK) activation by CD27

Summary

Introduction

CD27 is a member of the tumor necrosis factor receptor (TNF-R) superfamily and is expressed on T, B, and NK cells as a disulfide-linked homodimer [1]. TRAF2 participates in the activation of stress-activated kinase (SAPK)/c-Jun N-terminal kinase (JNK) induced by TNF (20 – 22). A serine/threonine kinase was identified that interacts with TRAF2 and activates NF-␬B, named NF-␬B-inducing kinase (NIK) [24]. We demonstrate that CD27 activates both NF-␬B and SAPK/JNK, which are mediated by TRAF2 and TRAF5. We demonstrate that a kinase-inactive mutant of NIK inhibited TRAF2-, TRAF5-, and CD27-mediated NF-␬B and SAPK/JNK activation. These results indicated a crucial role of TRAF2 and TRAF5 in CD27 signaling and that NIK is a common downstream kinase of TRAF2 and TRAF5 for NF-␬B and SAPK/JNK activation

Methods

Results

Conclusion