Rhbdd3 controls autoimmunity by suppressing the production of IL-6 by dendritic cells via K27-linked ubiquitination of the regulator NEMO.

Published

Journal Article

Excessive activation of dendritic cells (DCs) leads to the development of autoimmune and inflammatory diseases, which has prompted a search for regulators of DC activation. Here we report that Rhbdd3, a member of the rhomboid family of proteases, suppressed the activation of DCs and production of interleukin 6 (IL-6) triggered by Toll-like receptors (TLRs). Rhbdd3-deficient mice spontaneously developed autoimmune diseases characterized by an increased abundance of the TH17 subset of helper T cells and decreased number of regulatory T cells due to the increase in IL-6 from DCs. Rhbdd3 directly bound to Lys27 (K27)-linked polyubiquitin chains on Lys302 of the modulator NEMO (IKKγ) via the ubiquitin-binding-association (UBA) domain in endosomes. Rhbdd3 further recruited the deubiquitinase A20 via K27-linked polyubiquitin chains on Lys268 to inhibit K63-linked polyubiquitination of NEMO and thus suppressed activation of the transcription factor NF-κB in DCs. Our data identify Rhbdd3 as a critical regulator of DC activation and indicate K27-linked polyubiquitination is a potent ubiquitin-linked pattern involved in the control of autoimmunity.

Full Text

Duke Authors

Cited Authors

  • Liu, J; Han, C; Xie, B; Wu, Y; Liu, S; Chen, K; Xia, M; Zhang, Y; Song, L; Li, Z; Zhang, T; Ma, F; Wang, Q; Wang, J; Deng, K; Zhuang, Y; Wu, X; Yu, Y; Xu, T; Cao, X

Published Date

  • July 2014

Published In

Volume / Issue

  • 15 / 7

Start / End Page

  • 612 - 622

PubMed ID

  • 24859449

Pubmed Central ID

  • 24859449

Electronic International Standard Serial Number (EISSN)

  • 1529-2916

Digital Object Identifier (DOI)

  • 10.1038/ni.2898

Language

  • eng

Conference Location

  • United States