Diversity of amino acid signaling pathways on autophagy regulation: a novel pathway for arginine.
Autophagy is the intracellular bulk degradation process to eliminate damaged cellular machinery and to recycle building blocks, and is crucial for cell survival and cell death. Amino acids modulate autophagy in response to nutrient starvation and oxidative stress. We investigated the relevance of reactive oxygen species (ROS) production on the regulation of autophagy using amino acids, both as a mixture and individually, in rat hepatoma H4-II-E cells. Nutrient starvation elevated ROS production and stimulated autophagy. Treatment with complete (CAA), regulatory (RegAA) and non-regulatory (NonRegAA) amino acid mixtures showed significant suppression of ROS production, whereas only CAA and RegAA exhibited significant suppression of autophagy, suggesting a dissociation of the two responses. The effects of individual amino acids were examined. Leucine from RegAA decreased ROS production and suppressed autophagy. However, methionine and proline from RegAA and arginine, cystine and glutamic acid from NonRegAA suppressed autophagy with an opposite increase in ROS production. Other amino acids from the NonRegAA group showed stimulating effects on ROS production without an autophagic response. Arginine's effect on autophagy suppression was not blocked by rapamycin, indicating an mTOR-independent pathway. Inhibitor studies on arginine-regulated autophagy may indicate the involvement of NO pathway, which is independent from ROS and mTOR pathways.
Department of Applied Biological Chemistry, Faculty of Agriculture, Graduate School of Science and Technology, Japan.
Aileen B
AB
Angcajas
Department of Applied Biological Chemistry, Faculty of Agriculture, Graduate School of Science and Technology, Japan.
Norihiko
N
Hirai
Department of Applied Biological Chemistry, Faculty of Agriculture, Graduate School of Science and Technology, Japan.
Kenji
K
Kaneshiro
Department of Applied Biological Chemistry, Faculty of Agriculture, Graduate School of Science and Technology, Japan.
Md Razaul
MR
Karim
Department of Applied Biological Chemistry, Faculty of Agriculture, Graduate School of Science and Technology, Japan.
Yuichiro
Y
Horii
Center for Transdisciplinary Research, Niigata University, 2-8050 Ikarashi, Nishi-Ku, Niigata 950-2181, Japan.
Masatoshi
M
Kubota
Department of Applied Biological Chemistry, Faculty of Agriculture, Graduate School of Science and Technology, Japan; Center for Transdisciplinary Research, Niigata University, 2-8050 Ikarashi, Nishi-Ku, Niigata 950-2181, Japan.
Shinobu
S
Fujimura
Department of Applied Biological Chemistry, Faculty of Agriculture, Graduate School of Science and Technology, Japan; Center for Transdisciplinary Research, Niigata University, 2-8050 Ikarashi, Nishi-Ku, Niigata 950-2181, Japan. Electronic address: kadowaki@agr.niigata-u.ac.jp.
Motoni
M
Kadowaki
D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D056945:Hep G2 Cells; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000596:Amino Acids; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D001120:Arginine; C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
Amino acid signaling; Arginine; Autophagy; NO pathway; ROS