title: A proautophagic antiviral role for the cellular prion protein identified by infection with a herpes simplex virus 1 ICP34.5 mutant.
abstract: The cellular prion protein (PrP) often plays a cytoprotective role by regulating autophagy in response to cell stress. The stress of infection with intracellular pathogens can stimulate autophagy, and autophagic degradation of pathogens can reduce their replication and thus help protect the infected cells. PrP also restricts replication of several viruses, but whether this activity is related to an effect on autophagy is not known. Herpes simplex virus 1 (HSV-1) effectively counteracts autophagy through binding of its ICP34.5 protein to the cellular proautophagy protein beclin-1. Autophagy can reduce replication of an HSV-1 mutant, Δ68H, which is incapable of binding beclin-1. We found that deletion of PrP in mice complements the attenuation of Δ68H, restoring its capacity to replicate in the central nervous system (CNS) to wild-type virus levels after intracranial or corneal infection. Cultured primary astrocytes but not neurons derived from PrP(-/-) mice also complemented the attenuation of Δ68H, enabling Δ68H to replicate at levels equivalent to wild-type virus. Ultrastructural analysis showed that normal astrocytes exhibited an increase in the number of autophagosomes after infection with Δ68H compared with wild-type virus, but PrP(-/-) astrocytes failed to induce autophagy in response to Δ68H infection. Redistribution of EGFP-LC3 into punctae occurred more frequently in normal astrocytes infected with Δ68H than with wild-type virus, but not in PrP(-/-) astrocytes, corroborating the ultrastructural analysis results. Our results demonstrate that PrP is critical for inducing autophagy in astrocytes in response to HSV-1 infection and suggest that PrP positively regulates autophagy in the mouse CNS.
authors.affiliation: Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St Louis, Missouri, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Korom
authors.forename: Kristine M
authors.initials: KM
authors.lastname: Wylie
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Katie L
authors.initials: KL
authors.lastname: Davis
authors.forename: Meher S
authors.initials: MS
authors.lastname: Sangabathula
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Delassus
authors.forename: Lynda A
authors.initials: LA
authors.lastname: Morrison
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000821:virology; D001343:Autophagy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006561:Herpes Simplex / Q000473:pathology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000235:genetics; D000072002:Prion Proteins; D011328:Prions / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics*; D037521:Virulence Factors / Q000235:genetics
chemical_list: D050505:Mutant Proteins; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D014764:Viral Proteins; D037521:Virulence Factors; C066469:gamma 34.5 protein, Human herpesvirus 1