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Review
. 2020 Jul 29:10:384.
doi: 10.3389/fcimb.2020.00384. eCollection 2020.

Interplay Between Calcium and AMPK Signaling in Human Cytomegalovirus Infection

Diana M Dunn  1 , Joshua Munger  1
Affiliations
Review

Interplay Between Calcium and AMPK Signaling in Human Cytomegalovirus Infection

Diana M Dunn et al. Front Cell Infect Microbiol. .

Abstract

Calcium signaling and the AMP-activated protein kinase (AMPK) signaling networks broadly regulate numerous aspects of cell biology. Human Cytomegalovirus (HCMV) infection has been found to actively manipulate the calcium-AMPK signaling axis to support infection. Many HCMV genes have been linked to modulating calcium signaling, and HCMV infection has been found to be reliant on calcium signaling and AMPK activation. Here, we focus on the cell biology of calcium and AMPK signaling and what is currently known about how HCMV modulates these pathways to support HCMV infection and potentially contribute to oncomodulation.

Keywords: AMPK; HCMV; calcium signaling; cancer; cytomegalovirus; oncomodulation.

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Figures

Figure 1
Figure 1
Overview of calcium signaling. Calcium release from the extracellular space or intracellular compartments into the cytosol activates calmodulin, which in turn binds to CaMKK and CaMK proteins. Phosphorylation of CaM-binding proteins via autophosphorylation or upstream kinases further activates, or in some cases inhibits their activity toward downstream signaling proteins and transcription factors. The CaMKK inhibitor, STO-609, can also stall these downstream processes.
Figure 2
Figure 2
Overview of AMPK signaling. AMPK responds to low levels of ATP in the cell. First, AMP binds to the AMPKγ regulatory subunit causing a conformational change exposing threonine-172 in the AMPKα catalytic subunit. Then, Thr-172 is phosphorylated by upstream kinases, CaMKK, or LKB1, fully activating AMPK kinase activity toward substrates responsible for preserving cellular energy. AMPK can be activated by AICAR or metformin treatment, and inhibited by Compound C.
Figure 3
Figure 3
Calcium and AMPK signaling during HCMV infection. Calcium signaling contributes to increased intracellular calcium release through HCMV encoded genes, UL146, US28, UL37, and US21, and through viral entry via epidermal growth factor receptor (EGFR). HCMV infection also induces the expression of CaMKK and AMPK, both of which are crucial for viral replication through multiple cellular signals. HCMV infection also impacts neural cell development which is associated with loss of proper calcium response. Inhibition of CaMKK by STO-609 inhibits HMCV viral replication. AMPK inhibition by Compound C, or activation by metformin or AICAR, also results in a decrease in HCMV viral replication.
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