HCMV Targets the Metabolic Stress Response through Activation of AMPK Whose Activity Is Important for Viral Replication

McArdle, Jessica; Moorman, Nathaniel J.; Munger, Joshua

doi:10.1371/journal.ppat.1002502

Cited by 98 publications

(113 citation statements)

References 44 publications

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“…Recent studies have shown that eIF4F is required for the translation of several host metabolic enzymes (27). As HCMV infection remodels host metabolism (20,(33)(34)(35)(36), perhaps the increased eIF4F abundance and activity in infected cells promotes the expression of metabolic enzymes needed for virus replication.…”

Section: Discussionmentioning

confidence: 99%

Differential Role for Host Translation Factors in Host and Viral Protein Synthesis during Human Cytomegalovirus Infection

Lenarcic

Ziehr

Leon

et al. 2014

J Virol

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The host eIF4F translation initiation complex plays a critical role the translation of capped mRNAs. Although human cytomegalovirus (HCMV) infection increases the abundance and activity of the host eIF4F complex, the requirement for eIF4F components in HCMV replication and mRNA translation has not been directly tested. In this study, we found that decreasing the abundance or activity of eIF4F from the start of infection inhibits HCMV replication. However, as infection progresses, viral mRNA translation and replication becomes increasingly resistant to eIF4F inhibition. During the late stage of infection the association of representative immediate-early, early, and late mRNAs with polysomes was not affected by eIF4F disruption. In contrast, eIF4F inhibition decreased the translation of representative host eIF4F-dependent mRNAs during the late stage of infection. A global analysis of the translation efficiency of HCMV mRNAs during the late stage of infection found that eIF4F disruption had a minimal impact on the association of HCMV mRNAs with polysomes but significantly diminished the translation efficiency of eIF4F-dependent host transcripts. Together, our data show that the translation of host eIF4F-dependent mRNAs remains dependent on eIF4F activity during HCMV infection. However, during the late stage of infection the translation efficiency of viral mRNAs does not correlate with the abundance or activity of the host eIF4F complex.

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Section: Discussionmentioning

confidence: 99%

Differential Role for Host Translation Factors in Host and Viral Protein Synthesis during Human Cytomegalovirus Infection

Lenarcic

Ziehr

Leon

et al. 2014

J Virol

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“…In addition, it enables AMPK to be activated in response to acute energy insufficiency without concomitant mTORC1 inhibition. A distinct but related strategy operates in HCMV-infected cells whereby AMPK activation stimulates productive HCMV replication (7,9). Instead of the Us3 kinase, which is specific to alphaherpesviruses, HCMV encodes the TSC2 binding protein UL38 to antagonize TSC activity and stimulate mTORC1 (40).…”

Section: Discussionmentioning

confidence: 99%

“…Instead of the Us3 kinase, which is specific to alphaherpesviruses, HCMV encodes the TSC2 binding protein UL38 to antagonize TSC activity and stimulate mTORC1 (40). This precludes AMPK-mediated inhibition of mTORC1 while supporting AMPK-dependent metabolic changes conducive to virus reproduction (7,9). Compared to betaherpesviruses like HCMV, alphaherpesviruses have a very fast productive growth cycle that may not require AMPK activation.…”

Section: Discussionmentioning

confidence: 99%

Subversion of Host Responses to Energy Insufficiency by Us3 Supports Herpes Simplex Virus 1 Replication during Stress

Vink

Smiley

Mohr

2017

J Virol

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Cellular stress responses to energy insufficiency can impact virus reproduction. In particular, activation of the host AMP-activated protein kinase (AMPK) by low energy could limit protein synthesis by inhibiting mTORC1. Although many herpesviruses, including herpes simplex virus 1 (HSV-1), stimulate mTORC1, how HSV-1-infected cells respond to energy availability, a physiological indicator regulating mTORC1, has not been investigated. In addition, the impact of lowenergy stress on productive HSV-1 growth and viral genetic determinants potentially enabling replication under physiological stress remains undefined. Here, we demonstrate that mTORC1 activity in HSV-1-infected cells is largely insensitive to stress induced by simulated energy insufficiency. Furthermore, resistance of mTORC1 activity to low-energy-induced stress, while not significantly influenced by the HSV-1 UL46-encoded phosphatidylinositol 3-kinase (PI3K)-Akt activator, was dependent upon the Ser/Thr kinase activity of Us3. A Us3-deficient virus was hypersensitive to low-energy-induced stress as infected cell protein synthesis and productive replication were reduced compared to levels in cells infected with a Us3-expressing virus. Although Us3 did not detectably prevent energy stress-induced AMPK activation, it enforced mTORC1 activation despite the presence of activated AMPK. In the absence of applied low-energy stress, AMPK activity in infected cells was restricted in a Us3-dependent manner. This establishes that the Us3 kinase not only activated mTORC1 but also enabled sustained mTORC1 signaling during simulated energy insufficiency that would otherwise restrict protein synthesis and virus replication. Moreover, it identifies the alphaherpesvirus-specific Us3 kinase as an mTORC1 activator that subverts the host cell energy-sensing program to support viral productive growth irrespective of physiological stress.IMPORTANCE Like all viruses, herpes simplex virus type 1 (HSV-1) reproduction relies upon numerous host energy-intensive processes, the most demanding of which is protein synthesis. In response to low energy, the cellular AMP-activated protein kinase (AMPK) triggers a physiological stress response that antagonizes mTORC1, a multisubunit host kinase that controls protein synthesis. This could restrict virus protein production and growth. Here, we establish that the HSV-1 Us3 protein kinase subverts the normal response to low-energy-induced stress. While Us3 does not prevent AMPK activation by low energy, it enforces mTORC1 activation and overrides a physiological response that couples energy availability and protein synthesis. These results help explain how reproduction of HSV-1, a ubiquitous, medically significant human pathogen causing a spectrum of diseases ranging from the benign to the life threatening, occurs during physiological stress. This is important because HSV-1 reproduction triggered by physiological stress is characteristic of reactivation of lifelong latent infections.

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“…Some viruses stimulate an increase in host intracellular glucose levels to increase the energy available for replication by affecting signal transduction pathways associated with sugar metabolism (39,40). Intracellular Salmonellae have been shown to relay on host intracellular glucose (41).…”

Section: Discussionmentioning

confidence: 99%

Vibrio vulnificus Secretes an Insulin-degrading Enzyme That Promotes Bacterial Proliferation in Vivo

Kim

Wen

et al. 2015

Journal of Biological Chemistry

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Background: Vibrio vulnficus produces SidC, an extracellular insulin-degrading enzyme. Results: SidC causes degradation of insulin, leading to proliferation of the pathogen, and sidC was expressed in low-glucose conditions. Conclusion: Degradation of insulin by SidC correlated with the proliferation of the pathogen. Significance: V. vulnificus manipulates host endocrine signals through SidC, making the host environment more favorable for its own proliferation.

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HCMV Targets the Metabolic Stress Response through Activation of AMPK Whose Activity Is Important for Viral Replication

Cited by 98 publications

References 44 publications

Differential Role for Host Translation Factors in Host and Viral Protein Synthesis during Human Cytomegalovirus Infection

Differential Role for Host Translation Factors in Host and Viral Protein Synthesis during Human Cytomegalovirus Infection

Subversion of Host Responses to Energy Insufficiency by Us3 Supports Herpes Simplex Virus 1 Replication during Stress

Vibrio vulnificus Secretes an Insulin-degrading Enzyme That Promotes Bacterial Proliferation in Vivo

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