title: Rab12 regulates mTORC1 activity and autophagy through controlling the degradation of amino-acid transporter PAT4.
abstract: Autophagy is an evolutionarily conserved catabolic mechanism that targets intracellular molecules and damaged organelles to lysosomes. Autophagy is achieved by a series of membrane trafficking events, but their regulatory mechanisms are poorly understood. Here, we report small GTPase Rab12 as a new type of autophagic regulator that controls the degradation of an amino-acid transporter. Knockdown of Rab12 results in inhibition of autophagy and in increased activity of mTORC1 (mammalian/mechanistic target of rapamycin complex 1), an upstream regulator of autophagy. We also found that Rab12 promotes constitutive degradation of PAT4 (proton-coupled amino-acid transporter 4), whose accumulation in Rab12-knockdown cells modulates mTORC1 activity and autophagy. Our findings reveal a new mechanism of regulation of mTORC1 signalling and autophagy, that is, quality control of PAT4 by Rab12.
authors.affiliation: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Matsui
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Fukuda
mesh_terms: D026905:Amino Acid Transport Systems / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000502:physiology*
chemical_list: D026905:Amino Acid Transport Systems; D046912:Multiprotein Complexes; C583919:PAT4 protein, mouse; D034741:RNA, Small Interfering; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C569728:rab12 protein, mouse; D020691:rab GTP-Binding Proteins