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Review
. 2019 Dec 21;12(1):17.
doi: 10.3390/v12010017.

Herpesviruses and the Unfolded Protein Response

Benjamin P Johnston  1   2 , Craig McCormick  1   2
Affiliations
Review

Herpesviruses and the Unfolded Protein Response

Benjamin P Johnston et al. Viruses. .

Abstract

Herpesviruses usurp cellular stress responses to promote viral replication and avoid immune surveillance. The unfolded protein response (UPR) is a conserved stress response that is activated when the protein load in the ER exceeds folding capacity and misfolded proteins accumulate. The UPR aims to restore protein homeostasis through translational and transcriptional reprogramming; if homeostasis cannot be restored, the UPR switches from "helper" to "executioner", triggering apoptosis. It is thought that the burst of herpesvirus glycoprotein synthesis during lytic replication causes ER stress, and that these viruses may have evolved mechanisms to manage UPR signaling to create an optimal niche for replication. The past decade has seen considerable progress in understanding how herpesviruses reprogram the UPR. Here we provide an overview of the molecular events of UPR activation, signaling and transcriptional outputs, and highlight key evidence that herpesviruses hijack the UPR to aid infection.

Keywords: ATF4; ATF6; GADD34; IRE1; Kaposi’s sarcoma-associated herpesvirus (KSHV); PERK; XBP1; cytomegalovirus (CMV); herpes simplex virus (HSV); herpesvirus; integrated stress response (ISR); unfolded protein response (UPR).

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the writing of the manuscript.

Figures

Figure 1
Figure 1
Endoplasmic reticulum (ER) stress activates the unfolded protein response. The accumulation of misfolded proteins in the ER activates the unfolded protein response (UPR). UPR sensor proteins ATF6, IRE1, and PERK are normally restrained by binding to the ER chaperone BiP; ER stress displaces BiP and activates the sensors, thereby promoting synthesis of UPR transcription factors that coordinate an ER stress-mitigating gene expression program. Specifically, in response to ER stress, ATF6 translocates to the Golgi and is proteolytically cleaved by site-1 protease (S1P) and site-2 protease (S2P), releasing the N-terminal cytoplasmic transcription factor ATF6-N. IRE1 is a kinase and endoribonuclease that splices out a 26-nucleotide intron on XBP1 mRNA, which causes a translational frameshift to generate the transcription factor XBP1s. PERK phosphorylates eIF2α, which attenuates bulk translation thereby reducing protein load in the ER. Increased eIF2α phosphorylation also causes the selective translation of the transcription factor ATF4. ATF6-N, XBP1s, and ATF4 transactivate genes involved in protein folding, degradation of misfolded proteins, lipid synthesis, and antioxidant responses.
Figure 2
Figure 2
Kaposi’s sarcoma-associated herpesvirus (KSHV) reactivates from latency in response to ER stress. In response to ER stress, XBP1 mRNA is spliced and the XBP1s protein accumulates and translocates to the nucleus, where it transactivates the RTA gene encoding the lytic switch protein. RTA binds and transactivates viral early gene promoters throughout the genome and commits the virus to the lytic gene expression program and virion production.
Figure 3
Figure 3
KSHV activates UPR sensors but limits UPR gene expression during the lytic cycle. XBP1s is required for reactivation from latency in response to ER stress. All three UPR sensor proteins are activated in the early stages of lytic replication, but downstream UPR transcription is inhibited. ATF6-N is produced via proteolytic cleavage in the Golgi, but ATF6-N-responsive genes are not transcribed. IRE1 is activated and XBP1 is spliced, but XBP1s protein does not accumulate and XBP1s-responsive genes are not transcribed. eIF2α is phosphorylated in a PERK-dependent manner, but ATF4 protein does not accumulate and ATF4-responsive genes are not transcribed.
Figure 4
Figure 4
Differential control of the unfolded protein response by HCMV. In the early stages of HCMV lytic replication, PERK is activated by UL148 and UL38, which causes eIF2α phosphorylation and diminished global protein synthesis. At the same time, stress-dependent uORF skipping enables translation of the ATF4 bZIP transcription factor, which translocates to the nucleus and transactivates a variety of UPR genes. UL148 activates PERK as well as IRE1, which enables XBP1 splicing and synthesis of the XBP1s bZIP transcription factor that transactivates a distinct set of UPR genes. Later in the lytic cycle, the UL50 protein binds and downregulates IRE1 through an unknown mechanism, effectively shutting down IRE1-dependent UPR gene expression.
Figure 5
Figure 5
HSV-1 inhibits the UPR and the ISR. HSV-1 infection causes translocation of ATF6 to the Golgi apparatus, where is it cleaved by S1P and S2P to yield the ATF6-N bZIP transcription factor. Despite this, ATF6-N responsive genes are not transcribed in HSV-1 infected cells. HSV-1 triggers IRE1 kinase activity, but represses XBP1 splicing and XBP1s synthesis, and subsequent XBP1s-dependent transcription. HSV-1 glycoprotein B (gB) binds to PERK and prevents its activation, thereby limiting eIF2α phosphorylation and maintaining bulk protein synthesis. HSV-1 γ34.5 protein acts similarly to GADD34, recruiting the cellular PP1 phosphatase to eIF2a and reinforcing the blockade on ISR activation. As a result, ATF4 is not synthesized and ATF4-responsive genes remain dormant.
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