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

Abstract

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.

Cellular and molecular regulation of innate inflammatory responses

“…Mechanistically, Rhbdd3 localizes in early endosomes in DCs and interacts with K27-linked ubiquitination of NF-κB essential modifier (NEMO) and subsequently recruits A20 to facilitate A20-mediated K63-linked deubiquitination of NEMO. 72,73 By contrast, iRhom2, a novel noncatalytic relative of rhomboid proteins, facilitates LPS and Listeria-induced TNF production by promoting the TNF convertase (TACE) maturation and trafficking, 74,75 and also enhances innate immunity to DNA viruses by mediating STING trafficking and stability. 76 The differential regulation of innate immunity by Rhomboid family members awaits further investigation, and is likely to be related with their different subcellular localization that may provide specific biochemical and physical environment for specific signaling modifications.…”

Siglec1 suppresses antiviral innate immune response by inducing TBK1 degradation via the ubiquitin ligase TRIM27

“…Protein concentrations of the extracts were measured using a BCA assay (Pierce, Rockford, IL, USA) and equalized with the extraction reagent. Equivalent amounts of extracts were used for IP, or were loaded and subjected to SDS-PAGE, transferred onto nitrocellulose membranes, and then blotted as described previously [41]. For IP, whole-cell extracts were prepared after transfection or stimulation with appropriate ligands, followed by incubation overnight with the appropriate antibodies plus Protein A/G beads.…”

Platelets promote allergic asthma through the expression of CD154

“…Regulatory T cell (Treg) induction was carried out according to methods previously described 25 with minor modifications. CD4 1 T cells were enriched from C57BL/6 splenocytes via positive selection with magnetic beads, and the purity of enriched cells was confirmed to be over 90% by FACS.…”