Flavivirus Antagonism of Type I Interferon Signaling Reveals Prolidase as a Regulator of IFNAR1 Surface Expression

Kirk J. Lubick, Shelly J. Robertson, Kristin L. McNally, Brett A. Freedman, Angela L. Rasmussen, R. Travis Taylor, Avram D. Walts, Seitaro Tsuruda, Mizuki Sakai, Mariko Ishizuka, Elena F. Boer, Erin C. Foster, Abhilash I. Chiramel, Conrad B. Addison, Richard Green, Daniel L. Kastner, Michael G. Katze, Steven M. Holland, Antonella Forlino, Alexandra F. Freeman, Manfred Boehm, Kentaro Yoshii, and Sonja M. Best

Cell Host & Microbe 18, 61–74, July 8, 2015

Speaker: Chia-Yi Hung (洪嘉依)                              Time: 14:00~15:00, September 16, 2015

Commentator: Dr. Chia-Yi Yu (余佳益 老師)         Place: Room 601

Abstract:

The IFN-I receptor (IFNAR) is composed of two subunits, IFNAR1 and IFNAR2. Ligation of IFNAR by IFN-I results in the activation of a large group of genes, which are involved in host resistance to viral infection (1). The flaviviruses such as tick-borne encephalitis virus (TBEV), West Nile virus (WNV), and Japanese encephalitis virus (JEV) can cause severe encephalitides in humans, while dengue virus (DENV) and yellow fever virus (YFV) can cause hemorrhagic fevers. Despite their differences in pathogenicity, all of these flaviviruses utilize the nonstructural protein 5 (NS5) as a potent IFN-I antagonist. However, the molecular mechanisms of which it antagonizes JAK-STAT signaling are not well understood, particularly for TBEV and WNV. Previous study showed that replication of WNV is associated with loss of IFNAR1, implicating IFNAR1 as the target of viral interference (2). To further understand IFN-I antagonism, the authors determined whether loss of IFNAR1 is a common situation among these viruses. In this study, they found that TBEV and WNV antagonize IFN-I signaling by inhibiting IFNAR1 surface expression that involves NS5. In addition, they identified that the function of NS5 as an IFN-I antagonist is dependent on its ability to interact with prolidase (PEPD), a cellular dipeptidase. They demonstrated that PEPD is required for IFNAR1 expression and maturation as well as ISG mRNA expression following IFN-βstimulation. Finally, they examined primary fibroblasts from prolidase deficiency (PD) patients and found that low IFNAR1 expression is accompanied by deficiencies in IFN-I signaling, suggesting that PD is likely an unrecognized innate immune deficiency.

References:

1.         Perry AK, Chen G, Zheng D, Tang H and Cheng G. (2005) The host type I interferon response to viral and bacterial infections. Cell Res. 15: 407–422.

2.         Evans JD, Crown RA, Sohn JA