Multifaceted Role of AMPK in Viral Infections

Abstract

Viral pathogens often exploit host cell regulatory and signaling pathways to ensure an optimal environment for growth and survival. Several studies have suggested that 5'-adenosine monophosphate-activated protein kinase (AMPK), an intracellular serine/threonine kinase, plays a significant role in the modulation of infection. Traditionally, AMPK is a key energy regulator of cell growth and proliferation, host autophagy, stress responses, metabolic reprogramming, mitochondrial homeostasis, fatty acid β-oxidation and host immune function. In this review, we highlight the modulation of host AMPK by various viruses under physiological conditions. These intracellular pathogens trigger metabolic changes altering AMPK signaling activity that then facilitates or inhibits viral replication. Considering the COVID-19 pandemic, understanding the regulation of AMPK signaling following infection can shed light on the development of more effective therapeutic strategies against viral infectious diseases.

Keywords: AMPK; COVID-19; anabolic processes; apoptosis; autophagy; catabolic process; fatty acid metabolism; lipid metabolism; mitochondrial homeostasis; virus.

Figure 1

Functional domain of AMPK subunits. AMPK is a heterotrimeric complex composed of a catalytic α subunit(α1/2), regulatory β subunit (β1/2), and γ (γ1/2/3) subunit. AMPKα: kinase domain (KD) at the N-terminal contains Thr172, which is phosphorylated by upstream kinases; AID, auto-inhibitory domain; α-RIM: regulatory subunit interacting motif triggering conformational changes; β-subunit binding domain at the C-terminal. AMPKβ subunit: carbohydrate-binding module (CBM) near the N-terminal contains Ser108, which is important for the mechanism of action of some direct activators of AMPK; C-terminal domain containing the α-subunit-binding site and immediately followed by the domain for the γ-subunit interaction. αγ-binding domain: α-subunit-binding and γ-subunit interaction site at the C-terminal. AMPKγ subunit: cystathione-β-synthases (CBS) domain, which forms two Bateman domains containing four ATP/ADP/AMP-binding sites (CBS1–4).

Figure 2

Activation of AMPK by upstream kinases. AMPK is activated following the phosphorylation of Thr172 on the catalytic α-subunit by upstream kinases in response to shifting adenosine nucleotide levels, cytosolic calcium levels and external stressors. Following activation, AMPK regulates anabolic, ATP-consuming pathways and catabolic, ATP-generating pathways. A summary of the physiological roles of AMPK is listed above (arrow indicates activation/increase; bar indicates inhibition/decrease). LKB1, liver kinase B1; CAMKK2, calcium/calmodulin-dependent kinase kinase 2; TAK1, transforming growth factor-β-activated kinase 1; MLK3, mixed lineage kinase 3.

Figure 3

Summary of differentially expressed genes involved in the AMPK signaling pathway. Activation of AMPK occurs following phosphorylation of Thr172 (not shown) by LKB1, CaMKK, TAK1, and MLK3. Activated AMPK regulates glucose metabolism by increasing glucose uptake via translocation of GLUT4 by phosphorylating/inhibiting TBC1D1 and phosphorylating/activating PIKfyve, HDAC4, and PLD1. AMPK-mediated translocation of GLUT1 occurs following phosphorylation/inhibition of TXNIP. Glycolysis is stimulated via activation of PFKFB3, and glycogen storage is reduced by inhibition of GS. Inhibition of gluconeogenesis occurs following phosphorylation/inhibition of PDE4B, TORC2, HDAC4/5/6, and HNF4α. AMPK regulates lipid metabolism by phosphorylating/inhibiting HSL, HNF4α, and activating ATGL to increase lipolysis. An increase in β-oxidation occurs by phosphorylation of ACC2 and reducing fatty acid synthesis by phosphorylation of ACC1. AMPK decreases lipid and sterol synthesis by phosphorylating/inhibiting SREBP1, ChREBP, and HMGCR. AMPK inhibits protein synthesis by phosphorylating/inhibiting TIF-1α, mTORC1, and RAPTOR, and phosphorylating/activating eEF2K and TSC2, which inhibit mTORC1. Lastly, mitochondrial functions are regulated by activated AMPK by activating mitochondrial biosynthesis. AMPK phosphorylates/activates AKAP1, DRP1, PGC-1α, SIRT1, p53, and HDAC4. AMPK activates mitophagy and autophagy pathways by phosphorylating/activating ULK1, ACSS, Atg9, Beclin1, and FOXO3.

Figure 4

Categorizing viruses based on the effect of AMPK activation. Viral pathogens, sorted based on current literature, concerning whether activation of AMPK is beneficial or detrimental to the pathogens.