NFAR-1 and -2 modulate translation and are required for efficient host defense

doi:10.1073/pnas.0711222105

NFAR-1 and -2 modulate translation and are required for efficient host defense

*Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136;
Departments of ^†Cell Biology and
^‡Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and
^§Transgenic Mouse and Gene Targeting Core Facility, Emory University, Atlanta, GA 30322

Edited by Andrew V. Schally, Veterans Affairs Medical Center, Miami, FL, and approved January 25, 2008 (received for review November 27, 2007)

Abstract

We report here that the alternatively spliced nuclear factors associated with double-stranded RNA, NFAR-1 (90 kDa) and -2 (110 kDa), are involved in retaining cellular transcripts in intranuclear foci and can regulate the export of mRNA to the cytoplasm. Furthermore, the NFAR proteins were found to remain associated with exported ribonucleoprotein complexes. Loss of NFAR function, which was embryonic-lethal, caused an increase in protein synthesis rates, an effect augmented by the presence of the mRNA export factors TAP, p15, or Rae1. Significantly, NFAR depletion in normal murine fibroblasts rendered these cells dramatically susceptible to vesicular stomatitis virus replication. Collectively, our data demonstrate that the NFARs exert influence on mRNA trafficking and the modulation of translation rates and may constitute an innate immune translational surveillance mechanism important in host defense countermeasures against virus infection.

Footnotes

^¶To whom correspondence should be addressed. E-mail: gbarber{at}med.miami.edu
Author contributions: I.P. and R.E. contributed equally to this work; I.P., R.E., and G.N.B. designed research; I.P., R.E., M.F., P.A.F., D.R.N., I.S.L., B.M.A.F., and W.D.M. performed research; I.P., R.E., M.F., and P.A.F. analyzed data; and I.P. and G.N.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0711222105/DC1.