Modulation of the AMPK/Sirt1 Axis During Neuronal Infection by Herpes Simplex Virus Type 1

Martin, Carolina; Leyton, Luis; Arancibia, Yennyfer; Cuevas, Alexei; Zambrano, Ángara; Concha, Miguel; Otth, Carola

doi:10.3233/jad-140237

Cited by 28 publications

(32 citation statements)

References 52 publications

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“…Indirect immunofluorescence staining of fixed and permeabilized neuronal cells was performed as described (Martin et al, 2014b). Briefly, after fixation and permeabilization, cells were incubated with the corresponding primary antibodies diluted in PBS.…”

Section: Immunofluorescence Microscopymentioning

confidence: 99%

“…Recently, we showed that HSV-1 modulates the AMPK/Sirt1 axis during the course of neuronal infection (Martin et al, 2014b). In fact, during early infection (2 hpi) activated AMPK (p-AMPK) was down-regulated by the virus, possibly to favor viral protein translation, since p-AMPK inhibits mTORC1 pathway which is critical for the maintenance of cap-dependent translation (Shaw, 2009).…”

Section: Introductionmentioning

confidence: 98%

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Nutraceutical activators of AMPK/Sirt1 axis inhibit viral production and protect neurons from neurodegenerative events triggered during HSV-1 infection

et al. 2015

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Section: Immunofluorescence Microscopymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Nutraceutical activators of AMPK/Sirt1 axis inhibit viral production and protect neurons from neurodegenerative events triggered during HSV-1 infection

et al. 2015

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“…The roles of AMPK in the infection and replication of two members of herpesviruses, herpes simplex virus 1 (HSV-1) and human cytomegalovirus (HCMV), have been examined; however, the interactions of these viruses with the AMPK pathway appear to be complex (16)(17)(18)(19). At the early stage of infection (2 h postinfection), the AMPK activity was inhibited by HSV-1 infection; however, it gradually recovered as the infection progressed.…”

mentioning

confidence: 99%

“…At the early stage of infection (2 h postinfection), the AMPK activity was inhibited by HSV-1 infection; however, it gradually recovered as the infection progressed. AMPK agonist inhibited HSV-1 gene expression and viral production (17,19). Interestingly, both AMPK agonist and inhibitor impaired HCMV replication, suggesting that fine-tuning of AMPK activity might be essential for optimal HCMV replication (16,18).…”

mentioning

confidence: 99%

Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5′-AMP-Activated Protein Kinase

Cheng

Jung

et al. 2016

J Virol

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The host intracellular antiviral restriction factors inhibit viral infection and replication. The 5=-AMP-activated protein kinase (AMPK) is a cellular energy sensor regulating metabolic homeostasis. Activated AMPK inhibits the replication of numerous RNA viruses but enhances the entry of vaccinia virus. However, the role of AMPK in herpesvirus infection is unclear. In this study, we showed that the constitutive AMPK activity restricted Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication in primary human umbilical vein endothelial cells while KSHV infection did not markedly affect the endogenous AMPK activity. Knockdown of the AMPK␣1 considerably enhanced the expression of viral lytic genes and the production of infectious virions, while overexpression of a constitutively active AMPK had the opposite effects. Accordingly, an AMPK inhibitor, compound C, augmented viral lytic gene expressions and virion productions but an AMPK agonist, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), suppressed both. Furthermore, a common diabetes drug, metformin, which carries an AMPK-agonistic activity, drastically inhibited the expression of viral lytic genes and the production of infectious virions, suggesting the use of metformin as a therapeutic agent for KSHV infection and replication. Together, these results identify the host AMPK as a KSHV restriction factor that can serve as a potential therapeutic target. IMPORTANCEHost cells encode specific proteins to restrict viral infection and replication. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus associated with several cancers. In this study, we have identified 5=-AMP-activated protein kinase (AMPK), a cellular energy sensor, as a restriction factor of KSHV lytic replication during primary infection. Activation of AMPK suppresses, while inhibition of AMPK enhances, KSHV lytic replication by regulating the expression of viral genes. AICAR and metformin, both of which are AMPK agonists currently used in clinics for the treatment of conditions associated with metabolic disorders, inhibit KSHV lytic replication. Thus, our work has identified AMPK as a potential therapeutic target and AICAR and metformin as potential therapeutic agents for KSHV-associated cancers.

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“…In addition to Us3, which acts downstream of Akt to activate mTORC1, the UL46-encoded gene product VP11/12 interacts with the phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85 to stimulate Akt (22). While AMPK activation reportedly only modestly reduces virus replication in neurons, the capacity of HSV-1-encoded function(s) to antagonize AMPK activity, the identity of the function(s), and the mechanisms of action remain undefined (23,24).…”

mentioning

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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Modulation of the AMPK/Sirt1 Axis During Neuronal Infection by Herpes Simplex Virus Type 1

Cited by 28 publications

References 52 publications

Nutraceutical activators of AMPK/Sirt1 axis inhibit viral production and protect neurons from neurodegenerative events triggered during HSV-1 infection

Nutraceutical activators of AMPK/Sirt1 axis inhibit viral production and protect neurons from neurodegenerative events triggered during HSV-1 infection

Suppression of Kaposi's Sarcoma-Associated Herpesvirus Infection and Replication by 5′-AMP-Activated Protein Kinase

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

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