Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 42, Pages 11925-11930Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1601556113
Keywords
interferon; viral infection; TLR; RIG-I; TRAF3
Categories
Funding
- National Natural Science Foundation of China [81622030, 31570867, 31370017]
- Shandong Provincial Nature Science Foundation for Distinguished Young Scholars [JQ201420]
- Key Research and Development Program of Shandong Province [2015GSF118159]
- Fundamental Research Funds of Shandong University [2016JC023]
- National 973 Program of China [2011CB503906]
- Grants-in-Aid for Scientific Research [15K06829] Funding Source: KAKEN
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Type I IFNs (IFN-alpha/beta) play crucial roles in the elimination of invading viruses. Multiple immune cells including macrophages recognize viral infection through a variety of pattern recognition receptors, such as Toll-like receptors (TLRs) and retinoic acid-inducible gene-I (RIG-I)-like receptors, and initiate type I IFN secretion and subsequent antiviral immune responses. However, the mechanisms by which host immune cells can produce adequate amounts of type I IFNs and then eliminate viruses effectively remain to be further elucidated. In the present study, we show that munc18-1-interacting protein 3 (Mint3) expression can be markedly induced during viral infection in macrophages. Mint3 enhances TLR3/4- and RIG-I-induced IRF3 activation and IFN-beta production by promoting K63-linked polyubiquitination of TNF receptor-associated factor 3 (TRAF3). Consistently, Mint3 deficiency greatly attenuated antiviral immune responses and increased viral replication. Therefore, we have identified Mint3 as a physiological positive regulator of TLR3/4 and RIG-I-induced IFN-beta production and have outlined a feedback mechanism for the control of antiviral immune responses.
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