title: The herpes simplex virus 1 Us11 protein inhibits autophagy through its interaction with the protein kinase PKR.
abstract: Autophagy is now known to be an essential component of host innate and adaptive immunity. Several herpesviruses have developed various strategies to evade this antiviral host defense. Herpes simplex virus 1 (HSV-1) blocks autophagy in fibroblasts and in neurons, and the ICP34.5 protein is important for the resistance of HSV-1 to autophagy because of its interaction with the autophagy machinery protein Beclin 1. ICP34.5 also counteracts the shutoff of protein synthesis mediated by the double-stranded RNA (dsRNA)-dependent protein kinase PKR by inhibiting phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) in the PKR/eIF2α signaling pathway. Us11 is a late gene product of HSV-1, which is also able to preclude the host shutoff by direct inhibition of PKR. In the present study, we unveil a previously uncharacterized function of Us11 by demonstrating its antiautophagic activity. We show that the expression of Us11 is able to block autophagy and autophagosome formation in both HeLa cells and fibroblasts. Furthermore, immediate-early expression of Us11 by an ICP34.5 deletion mutant virus is sufficient to render the cells resistant to PKR-induced and virus-induced autophagy. PKR expression and the PKR binding domain of Us11 are required for the antiautophagic activity of Us11. However, unlike ICP34.5, Us11 did not interact with Beclin 1. We suggest that the inhibition of autophagy observed in cells infected with HSV-1 results from the activity of not only ICP34.5 on Beclin 1 but also Us11 by direct interaction with PKR.
authors.affiliation: INSERM UMR984, Université Paris Sud, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Lussignol
authors.forename: Christophe
authors.initials: C
authors.lastname: Queval
authors.forename: Marie-Françoise
authors.initials: MF
authors.lastname: Bernet-Camard
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cotte-Laffitte
authors.forename: Isabelle
authors.initials: I
authors.lastname: Beau
authors.forename: Patrice
authors.initials: P
authors.lastname: Codogno
authors.forename: Audrey
authors.initials: A
authors.lastname: Esclatine
mesh_terms: D001343:Autophagy; D002460:Cell Line; D004847:Epithelial Cells / Q000502:physiology / Q000821:virology; D005347:Fibroblasts / Q000502:physiology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D016601:RNA-Binding Proteins; C074546:US11 protein, herpesvirus; D014764:Viral Proteins; D019892:eIF-2 Kinase