Murine gammaherpesvirus 68 open reading frame 75c tegument protein induces the degradation of PML and is essential for production of infectious virus.
Promyelocytic Leukemia nuclear body (PML NB) proteins mediate an intrinsic cellular host defense response against virus infections. Herpesviruses express proteins that modulate PML or PML-associated proteins by a variety of strategies, including degradation of PML or relocalization of PML NB proteins. The consequences of PML-herpesvirus interactions during infection in vivo have yet to be investigated in detail, largely because of the species-specific tropism of many human herpesviruses. Murine gammaherpesvirus 68 (gammaHV68) is emerging as a suitable model to study basic biological questions of virus-host interactions because it naturally infects mice. Therefore, we sought to determine whether gammaHV68 targets PML NBs as part of its natural life cycle. We found that gammaHV68 induces PML degradation through a proteasome-dependent mechanism and that loss of PML results in more robust virus replication in mouse fibroblasts. Surprisingly, gammaHV68-mediated PML degradation was mediated by the virion tegument protein ORF75c, which shares homology with the cellular formylglycinamide ribotide amidotransferase enzyme. In addition, we show that ORF75c is essential for production of infectious virus. ORF75 homologs are conserved in all rhadinoviruses but so far have no assigned functions. Our studies shed light on a potential role for this unusual protein in rhadinovirus biology and suggest that gammaHV68 will be a useful model for investigation of PML-herpesvirus interactions in vivo.
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Mail Stop BCM-385, One Baylor Plaza, Houston, Texas 77030, USA. pling@bcm.edu
Paul D
PD
Ling
Jie
J
Tan
Jaturong
J
Sewatanon
RongSheng
R
Peng
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D018142:Gammaherpesvirinae / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000378:metabolism; D016366:Open Reading Frames; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex