期刊
NATURE IMMUNOLOGY
卷 15, 期 7, 页码 612-622出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2898
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资金
- National Key Basic Research Program of China [2013CB530503, 2012CB910202]
- National Natural Science Foundation of China [81230074, 81123006, 81172787]
- National 125 Key Project [2012AA020901]
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 T(H)17 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 (IKK gamma) 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-kappa B 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.
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