AMP-Activated Protein Kinase and Host Defense against Infection

Abstract

5'-AMP-activated protein kinase (AMPK) plays diverse roles in various physiological and pathological conditions. AMPK is involved in energy metabolism, which is perturbed by infectious stimuli. Indeed, various pathogens modulate AMPK activity, which affects host defenses against infection. In some viral infections, including hepatitis B and C viral infections, AMPK activation is beneficial, but in others such as dengue virus, Ebola virus, and human cytomegaloviral infections, AMPK plays a detrimental role. AMPK-targeting agents or small molecules enhance the antiviral response and contribute to the control of microbial and parasitic infections. In addition, this review focuses on the double-edged role of AMPK in innate and adaptive immune responses to infection. Understanding how AMPK regulates host defenses will enable development of more effective host-directed therapeutic strategies against infectious diseases.

Keywords: AMPK; host defense; infection; mycobacteria.

Figure 1

Domain structures of the 5′ AMP-activated protein kinase (AMPK) subunits and the mechanisms that regulate activation of AMPK signaling pathways. (A) Conserved domain structure of AMPK subunits consisting of a catalytic α subunit, scaffolding β subunit, and regulatory γ subunit. AID, autoinhibitory domain; CBM, carbohydrate-binding module; CBS, cystathionine-beta-synthase; CTD, C-terminal domain. (B) AMPK is activated by the upstream kinases LKB1, CAMKK2 and TAK1 associated with the canonical pathway (triggered by an increased cellular AMP/ATP ratio) or the non-canonical pathway (triggered by an increased intracellular Ca²⁺ concentration or infection/TLR activation). Activated AMPK modulates cellular homeostasis, such as energy metabolism and autophagy, and mitochondrial homeostasis. (black arrow indicate activation/increase; bar-headed red arrow indicates inhibition/decrease). CAMKK2, calcium/calmodulin-dependent kinase kinase 2; LKB1, liver kinase B1; TAK1, Transforming growth factor-β-activated kinase 1; TLR, Toll-like receptor.

Figure 1

Domain structures of the 5′ AMP-activated protein kinase (AMPK) subunits and the mechanisms that regulate activation of AMPK signaling pathways. (A) Conserved domain structure of AMPK subunits consisting of a catalytic α subunit, scaffolding β subunit, and regulatory γ subunit. AID, autoinhibitory domain; CBM, carbohydrate-binding module; CBS, cystathionine-beta-synthase; CTD, C-terminal domain. (B) AMPK is activated by the upstream kinases LKB1, CAMKK2 and TAK1 associated with the canonical pathway (triggered by an increased cellular AMP/ATP ratio) or the non-canonical pathway (triggered by an increased intracellular Ca²⁺ concentration or infection/TLR activation). Activated AMPK modulates cellular homeostasis, such as energy metabolism and autophagy, and mitochondrial homeostasis. (black arrow indicate activation/increase; bar-headed red arrow indicates inhibition/decrease). CAMKK2, calcium/calmodulin-dependent kinase kinase 2; LKB1, liver kinase B1; TAK1, Transforming growth factor-β-activated kinase 1; TLR, Toll-like receptor.

Figure 2

Multifaceted roles of AMPK in viral and bacterial infections. A variety of viruses and bacteria modulate host AMPK activity to promote their growth in host cells. Activation of the AMPK signaling pathway has been implicated in both beneficial antiviral (left upper) and detrimental proviral (right upper) responses. In addition, AMPK activation promotes the host response to infections by various bacteria (left lower) but, in some cases, promotes a detrimental response (right lower). The detailed mechanisms by which AMPK activation/inhibition affects infection outcomes are listed in Table 1, Table 2, Table 3 and Table 4.

Figure 3

Regulatory effects and underlying mechanisms of small-molecule AMPK activators on the innate immune and inflammatory responses. (red upward arrows indicate activation/increase and blue downward arrows indicate inhibition/decrease)