Faculty Collaboration Database

CCR5-Dependent Activation of mTORC1 Regulates Translation of Inducible NO Synthase and COX-2 during Encephalomyocarditis Virus Infection. J Immunol 2015 Nov 01;195(9):4406-14

Date

09/27/2015

Pubmed ID

26408666

Pubmed Central ID

PMC4610876

DOI

10.4049/jimmunol.1500704

Scopus ID

2-s2.0-84945162363 (requires institutional sign-in at Scopus site)   11 Citations

Abstract

Encephalomyocarditis virus (EMCV) infection of macrophages results in the expression of a number of inflammatory and antiviral genes, including inducible NO synthase (iNOS) and cyclooxygenase (COX)-2. EMCV-induced macrophage activation has been shown to require the presence of CCR5 and the activation of PI3K-dependent signaling cascades. The purpose of this study was to determine the role of PI3K in regulating the macrophage responses to EMCV. We show that PI3K regulates EMCV-stimulated iNOS and COX-2 expression by two independent mechanisms. In response to EMCV infection, Akt is activated and regulates the translation of iNOS and COX-2 through the mammalian target of rapamycin complex (mTORC)1. The activation of mTORC1 during EMCV infection is CCR5-dependent and appears to function in a manner that promotes the translation of iNOS and COX-2. CCR5-dependent mTORC1 activation functions as an antiviral response, as mTORC1 inhibition increases the expression of EMCV polymerase. PI3K also regulates the transcriptional induction of iNOS and COX-2 in response to EMCV infection by a mechanism that is independent of Akt and mTORC1 regulation. These findings indicate that macrophage expression of the inflammatory genes iNOS and COX-2 occurs via PI3K- and Akt-dependent translational control of mTORC1 and PI3K-dependent, Akt-independent transcriptional control.

Author List

Shaheen ZR, Naatz A, Corbett JA

Author

John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blotting, Western
Cell Line
Cells, Cultured
Cyclooxygenase 2
Encephalomyocarditis virus
Gene Expression Regulation
Host-Pathogen Interactions
Interferon-gamma
Macrophages
Male
Mechanistic Target of Rapamycin Complex 1
Mice, Inbred C57BL
Mice, Knockout
Multiprotein Complexes
Nitric Oxide Synthase Type II
Phosphatidylinositol 3-Kinases
Protein Biosynthesis
Proto-Oncogene Proteins c-akt
Receptors, CCR5
Reverse Transcriptase Polymerase Chain Reaction
TOR Serine-Threonine Kinases