title: Mdm20 Modulates Actin Remodeling through the mTORC2 Pathway via Its Effect on Rictor Expression.
abstract: NatB is an N-terminal acetyltransferase consisting of a catalytic Nat5 subunit and an auxiliary Mdm20 subunit. In yeast, NatB acetylates N-terminal methionines of proteins during de novo protein synthesis and also regulates actin remodeling through N-terminal acetylation of tropomyosin (Trpm), which stabilizes the actin cytoskeleton by interacting with actin. However, in mammalian cells, the biological functions of the Mdm20 and Nat5 subunits are not well understood. In the present study, we show for the first time that Mdm20-knockdown (KD), but not Nat5-KD, in HEK293 and HeLa cells suppresses not only cell growth, but also cellular motility. Although stress fibers were formed in Mdm20-KD cells, and not in control or Nat5-KD cells, the localization of Trpm did not coincide with the formation of stress fibers in Mdm20-KD cells. Notably, knockdown of Mdm20 reduced the expression of Rictor, an mTORC2 complex component, through post-translational regulation. Additionally, PKCαS657 phosphorylation, which regulates the organization of the actin cytoskeleton, was also reduced in Mdm20-KD cells. Our data also suggest that FoxO1 phosphorylation is regulated by the Mdm20-mTORC2-Akt pathway in response to serum starvation and insulin stimulation. Taken together, the present findings suggest that Mdm20 acts as a novel regulator of Rictor, thereby controlling mTORC2 activity, and leading to the activation of PKCαS657 and FoxO1.
authors.affiliation: The Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: The Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: The Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Mori
mesh_terms: D000123:Acetyltransferases / Q000172:deficiency / Q000378:metabolism; D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D063210:N-Terminal Acetyltransferase B / Q000172:deficiency / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D002352:Carrier Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D046912:Multiprotein Complexes; C570949:NAA25 protein, human; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000123:Acetyltransferases; C556312:NatB protein, S cerevisiae; D063210:N-Terminal Acetyltransferase B; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases