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 doublestranded RNA (dsRNA)-dependent protein kinase PKR by inhibiting phosphorylation of the eukaryotic translation initiation factor 2␣ (eIF2␣) in the PKR/eIF2␣ 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.

Autophagy interaction with herpes simplex virus type-1 infection

“…Despite seemingly discrepant findings, it is plausible to speculate that an alternative mechanism other than xenophagic degradation might be involved in the immune control by autophagy, especially considering the well-accepted fact that HSV-1 suppresses cellular autophagy in a multitude of ways. 28,29,32,33 Other than the controversial xenophagic degradation, autophagic influence is observed in both major histocompatibility complex class I (MHC-I) and class II (MHC-II) antigen presentation pathways, which aids adaptive immune activation. 33,34 Infection with mutant HSV-1, which is defective in BECN1 binding and therefore in counteracting autophagy, stimulates a more robust HSV-1-specific CD4 C T cell response in vivo, as compared to its marker-rescued wild-type counterpart.…”

“…In addition to ICP34.5, tegument protein Us11 has also been implicated in the regulation of the autophagy pathway. 32 Us11 is an abundant viral protein produced in the late stage of the viral life cycle, which physically interacts with EIF2AK2 to prevent EIF2AK2-mediated phosphorylation of EIF2S1 (Fig. 1).…”

“…47,48 A recent study by Lussignol et al, showed that immediate-early expression of Us11 renders cells infected with ICP34.5-null HSV-1 resistant to EIF2AK2-elicited autophagy. 32 Moreover, ectopic expression of Us11 fails to block autophagy in EIF2AK2-deficient cells in vitro, 32 suggestive of a EIF2AK2-dependent effect of Us11 on autophagy regulation. However, the in vivo relevance of this finding and the underlying mechanism of Us11-mediated inhibition of cellular autophagy need to be further investigated.…”

Herpes simplex virus types 1 and 2 modulate autophagy in SIRC corneal cells

“…HSV-1 and HSV-2 are also capable of modulating autophagy, termed type II programmed cell death (Tallóczy et al 2001;Tallóczy et al 2006;McFarlane et al 2011;Lussignol et al 2013). Autophagy is an essential catabolic process that maintains cellular integrity by degrading cytoplasmic constituents and organelles (Deretic and Levine 2009).…”

“…It has been shown that at the early stage of infection HSV-1 provokes autophagy (McFarlane et al 2011). However, some viral proteins (ICP34.5 and US11) synthesized during the subsequent phases of productive infection function as powerful inhibitors of the autophagic process (Tallóczy et al 2001;Tallóczy et al 2006;Orvedahl et al 2007;Lussignol et al 2013). ICP34.5 of HSV-1 antagonizes autophagy by binding Beclin-1, and by blocking the double-stranded RNA-dependent protein kinase/eukaryotic translation initiation factor 2α (PKR/ eIF2α) pathway (Tallóczy et al 2006;Orvedahl et al 2007).…”