Functional Amino Acids and Autophagy: Diverse Signal Transduction and Application

Abstract

Functional amino acids provide great potential for treating autophagy-related diseases by regulating autophagy. The purpose of the autophagy process is to remove unwanted cellular contents and to recycle nutrients, which is controlled by many factors. Disordered autophagy has been reported to be associated with various diseases, such as cancer, neurodegeneration, aging, and obesity. Autophagy cannot be directly controlled and dynamic amino acid levels are sufficient to regulate autophagy. To date, arginine, leucine, glutamine, and methionine are widely reported functional amino acids that regulate autophagy. As a signal relay station, mammalian target of rapamycin complex 1 (mTORC1) turns various amino acid signals into autophagy signaling pathways for functional amino acids. Deficiency or supplementation of functional amino acids can immediately regulate autophagy and is associated with autophagy-related disease. This review summarizes the mechanisms currently involved in autophagy and amino acid sensing, diverse signal transduction among functional amino acids and autophagy, and the therapeutic appeal of amino acids to autophagy-related diseases. We aim to provide a comprehensive overview of the mechanisms of amino acid regulation of autophagy and the role of functional amino acids in clinical autophagy-related diseases and to further convert these mechanisms into feasible therapeutic applications.

Keywords: autophagy; autophagy-related diseases; functional amino acids; mTORC1; signal transduction.

Figure 1

Mechanisms of autophagy induction. The ULK1 complex, PtdIns(3)K complex, and two ubiquitination systems are involved in the formation of autophagosomes. Atg14 promotes the formation of STX17-SNAP29-VAMP8-reconstituted proteoliposomes to form autolysosomes.

Figure 2

Classical amino acid sensing pathways regulate autophagy. (A) The abundant amino acids activate the Ragulator complex to promote the most active amino acid sensors, including SLC38A9, LRS, and FLCN-FNIP to RagGTPases, in which RagA/B binds to GTP and RagC/D to GDP, which recruits mTORC1 to the lysosome and is activated, thereby inhibiting autophagy. (The red arrow refers to the caption below, meaning the mTORC1 is activated in the lysosome.) (B) The mTORC1 activated by the abundant amino acids inhibits autophagy-related proteins, which are related with autophagy initiation, autophagosome formation, autophagosome maturation and autolysosome formation. (C) Amino acid starvation prevents the translocation of mTORC1 to the surface of the lysosome and inhibits its activity. GCN2 kinase binds to the elevated uncharged tRNA to be activated, then phosphorylates eIF2α and upregulates the transcriptional activities of ATF4 and CHOP to induce autophagy.

Figure 3

The mTORC1 mediates signal transduction of functional amino acids regulating autophagy; mTORC1 is an intracellular signal transfer station for amino acid regulation of mTORC1-dependent autophagy. (A) CASTOR1 senses and binds to arginine, which promotes the translocation and activation of mTORC1 to the lysosomes. SLC38A9 senses arginine in lysosomes and is required for the transfer of leucine out of lysosomes to activate mTORC1. The TM4SF5-mTORC1-SLC38A9 complex, together with LAAT1, facilitates the transfer of arginine out of lysosome. (B) Sestrin2 senses leucine in a manner similar to CASTOR1. LRS activates mTORC1 by activating RagGTPase or PLD1. The leucine metabolite acetyl-CoA acetylates the Raptor at K1097 via EP300. GLUD1 also contributes to the regulation of autophagy by leucine. (C) Arf1 GTPase participates in glutamine-mediated mTORC1 activation. (D) Methionine promotes the activation of GlyRS and activates NFκB1 to elevate the expression of mTORC1. T1R1/T1R3 senses extracellular methionine to stimulate ERK1/2 activation by enhancing the Ca²⁺ concentration and then activates mTORC1.

Figure 4

Specific amino acids regulate autophagy by inhibiting mTORC1 and increasing LC3-II expression. (The red arrow connects the left to right side of the diagram, representing the transition from mechanism to function; plus signs are used to present that amino acids promote autophagy.) (A) Arginine deficiency has been shown to upregulate autophagy via diverse pathways. (B) Leucine deficiency fails to induce autophagy in melanoma due to an overactivated RAS-MEK pathway. Leucine deficiency and its metabolite acetyl-CoA induce autophagy through mTORC1 in other cell types such as 293T cells and MEFs. (C) Glutamine-metabolizing enzymes GLS, GDH, and GS, which are enhanced by FOXO3 in Ba/F3 cells, are involved in glutamine synthesis and glutaminolysis. Glutaminolysis produces ammonia and α-ketoglutarate, ammonia promotes mTORC1-independent autophagy, and α-ketoglutarate inhibits mTORC1-dependent autophagy. Glutamine starvation upregulates SLC7A5 expression, increases intracellular uptake of leucine, activates mTORC1, and inhibits autophagy. (D) Knocking out MsrA increased p62-positive inclusion bodies and upregulated LC3-II expression in VSMC. SAM, synthesized from methionine, methylates PP2A to dephosphorylate the substrate Npr2p, thereby releasing the inhibition of mTORC1 by Npr2p, which suppresses NNS-autophagy.