Amino Acid Sensing via General Control Nonderepressible-2 Kinase and Immunological Programming

Abstract

Metabolic adaptation to the changing nutrient levels in the cellular microenvironment plays a decisive role in the maintenance of homeostasis. Eukaryotic cells are equipped with nutrient sensors, which sense the fluctuating nutrients levels and accordingly program the cellular machinery to mount an appropriate response. Nutrients including amino acids play a vital role in maintaining cellular homeostasis. Therefore, over the evolution, different species have developed diverse mechanisms to detect amino acids abundance or scarcity. Immune responses have been known to be closely associated with the cellular metabolism especially amino acid sensing pathway, which influences innate as well as adaptive immune-effector functions. Thus, exploring the cross-talk between amino acid sensing mechanisms and immune responses in disease as well as in normal physiological conditions might open up avenues to explore how this association can be exploited to tailor immunological functions toward the design of better therapeutics for controlling metabolic diseases. In this review, we discuss the advances in the knowledge of various amino acid sensing pathways including general control nonderepressible-2 kinase in the control of inflammation and metabolic diseases.

Keywords: amino acid sensing; general control nonderepressible-2 kinase; immune response; inflammation; mammalian target of rapamycin; metabolic diseases.

Figure 1

Amino acid sensing and integration of downstream pathways. Schematic representation of the cellular events during amino acid-deficient and amino acid sufficient conditions. General control nonderepressible-2 kinase senses amino acid insufficiency and orchestrate various homeostatic processes via eIF2 phosphorylation followed by downregulation of global protein synthesis and simultaneously also inhibits mammalian target of rapamycin (mTOR) activation. On the other hand, under the condition of amino acid sufficiency, mTORC1 complex translocates to lysosomal surfaces by virtue of Rag GTPase activation and further initiates protein translation by the release of translation initiation factor eIF4E.

Figure 2

General control nonderepressible-2 kinase (GCN2)-mediated amino acid sensing in the control of inflammation during cellular stress. Amino acid deficiency leads to accumulation of uncharged tRNAs, which are recognized by the nutrient sensor GCN2. Upon its activation, the phospho-GCN2 inhibits the translation initiation ternary complex through the phosphorylation of eIF2α, thus stalls the protein translation. As a result, the RNA-binding proteins are recruited to the translationally stalled mRNAs, forming stress granules that either arrest or decay the stalled mRNAs, and ultimately decreasing the inflammation. At the same time eIF2 phosphorylation leads to translation of specific mRNA, such as ATF4, which translates stress-response genes, GADD34, CHOP, etc. On the other hand, GCN2 pathway induces autophagy which reduces inflammation through inhibition of the reactive oxygen species and inflammasome activation.

Figure 3

Amino acid sensing and cellular Th17-immune responses. General control nonderepressible-2 kinase (GCN2)-mediated amino acid sensing is also known to dampen the Th17 immune responses by inhibiting the STAT3 transcription factor, essential for Th17 response and simultaneously by hindering the mTORC1 activity, which is known to facilitate Th17 differentiation via S6K2 activation followed by nuclear translocation of RORγ. The GCN2 activation also leads to activation and differentiation of the regulatory T cells.