Interplay Between Calcium and AMPK Signaling in Human Cytomegalovirus Infection

Dunn, Derek; Munger, Joshua

doi:10.3389/fcimb.2020.00384

Cited by 19 publications

(11 citation statements)

References 157 publications

(185 reference statements)

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“…However, knockdown of AMPK led itself to impaired production of viral progeny (Figure 5C), in line with previous reports (Terry et al, 2012). A tight and timely regulation of AMPK is likely crucial for HCMV infection since both chemical AMPK activation and inhibition are known to inhibit HCMV propagation (Kudchodkar et al, 2007;Terry et al, 2012;Dunn et al, 2020). In our proposed model, PP1 inhibition by 1E7-03 leads to early AMPK activation and EEF2 inactivation, followed by attenuated translation and inhibition of lytic HCMV infection (Figure 5D).…”

Section: Pp1 Is Necessary For Mitogenic Activation Via Eef2 In Infected Cellssupporting

confidence: 90%

Protein Phosphatase 1 Regulates Human Cytomegalovirus Protein Translation by Restraining AMPK Signaling

et al. 2021

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Human cytomegalovirus (HCMV) carries the human protein phosphatase 1 (PP1) and other human proteins important for protein translation in its tegument layer for a rapid supply upon infection. However, the biological relevance behind PP1 incorporation and its role during infection is unclear. Additionally, PP1 is a difficult molecular target due to its promiscuity and similarities between the catalytic domain of multiple phosphatases. In this study, we circumvented these shortcomings by using 1E7-03, a small molecule protein–protein interaction inhibitor, as a molecular tool of noncatalytic PP1 inhibition. 1E7-03 treatment of human fibroblasts severely impaired HCMV replication and viral protein translation. More specifically, PP1 inhibition led to the deregulation of metabolic signaling pathways starting at very early time points post-infection. This effect was at least partly mediated by the prevention of AMP-activated protein kinase dephosphorylation, leading to elongation factor 2 hyperphosphorylation and reduced translation rates. These findings reveal an important mechanism of PP1 for lytic HCMV infection.

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Section: Pp1 Is Necessary For Mitogenic Activation Via Eef2 In Infected Cellssupporting

confidence: 90%

Protein Phosphatase 1 Regulates Human Cytomegalovirus Protein Translation by Restraining AMPK Signaling

et al. 2021

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“…However, at low concentrations of caffeine, Ca 2+ release is dependent on extracellular calcium. , The release of the internal storage of calcium into the cytoplasm activates the CaMKK kinase activity, leading to activation of AMPK. This, in turn, inhibits mTOR, leading to the activation of autophagy. , The four natural products studied in our experiments showed pain reduction in phase 2 of the formalin-induced pain model. This reveals that they can be used to treat inflammation and pain in many acute and chronic conditions.…”

Section: Discussionmentioning

confidence: 63%

Autophagy: An Emerging Target for Developing Effective Analgesics

Manivasakam¹,

Ravi

Janani

et al. 2023

ACS Omega

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Inadequate treatment of acute and chronic pain causes depression, anxiety, sleep disturbances, and increased mortality. Abuse and overdose of opioids and the side effects associated with chronic use of NSAID illustrate the need for development of safer and effective pain medication. Working toward this end, an in silico tool based on an emergent intelligence analytical platform that examines interactions between protein networks was used to identify molecular mechanisms involved in regulating the body's response to painful stimuli and drug treatments. Examining interactions between protein networks associated with the expression of over 20 different pain types suggests that the regulation of autophagy plays a central role in modulation of pain symptoms (see Materials and Methods). Using the topology of this regulatory scheme as an in silico screening tool, we identified that combinations of functions targeted by cannabidiol, myo-inositol, and fish oils with varying ratios of eicosapentaenoic and docosahexaenoic acids are projected to produce superior analgesia. For validating this prediction, we administered combinations of cannabidiol, myo-inositol, and fish oils to rats that received formalin injections in hind paws, prior to substance administration, and showed that analgesic effects produced by these combinations were comparable or superior to known NSAID analgesics, which suggests that these combinations have potential in treatment of pain.

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“…Interestingly, the activation of glycolysis via UL38 is dependent on its ability to inhibit TSC2 ( 80 ), suggesting interplay between this viral protein and the AMPK pathway. Additionally, HCMV proteins such as UL37, US28, US21, and UL146, which regulate calcium signaling, could indirectly activate the AMPK pathway due to significant overlaps in the downstream consequences of AMPK and calcium signaling ( 82 ).…”

Section: Ampk Pathwaymentioning

confidence: 99%