Journal
CELL HOST & MICROBE
Volume 18, Issue 1, Pages 61-74Publisher
CELL PRESS
DOI: 10.1016/j.chom.2015.06.007
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Funding
- Intramural Research Program of the National Institutes of Health
- NIAID
- NHGRI
- NHLBI, Italian Cariplo [2011-0270]
- NIAID/NIH Grant [U19 AI109761]
- Ministry of Education, Culture, Sports, Sciences and Technology of Japan [22780268, 24780293, 26660220]
- Akiyama Life Science Foundation
- Grants-in-Aid for Scientific Research [26660220, 24780293] Funding Source: KAKEN
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Type I interferon (IFN-alpha/beta or IFN-I) signals through two receptor subunits, IFNAR1 and IFNAR2, to orchestrate sterile and infectious immunity. Cellular pathways that regulate IFNAR1 are often targeted by viruses to suppress the antiviral effects of IFN-I. Here we report that encephalitic flaviviruses, including tick-borne encephalitis virus and West Nile virus, antagonize IFN-I signaling by inhibiting IFNAR1 surface expression. Loss of IFNAR1 was associated with binding of the viral IFN-I antagonist, NS5, to prolidase (PEPD), a cellular dipeptidase implicated in primary immune deficiencies in humans. Prolidase was required for IFNAR1 maturation and accumulation, activation of IFN beta-stimulated gene induction, and IFN-I-dependent viral control. Human fibroblasts derived from patients with genetic prolidase deficiency exhibited decreased IFNAR1 surface expression and reduced IFN beta-stimulated signaling. Thus, by understanding flavivirus IFN-I antagonism, prolidase is revealed as a central regulator of IFN-I responses.
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