title: Mdm20 stimulates polyQ aggregation via inhibiting autophagy through Akt-Ser473 phosphorylation.
abstract: Mdm20 is an auxiliary subunit of the NatB complex, which includes Nat5, the catalytic subunit for protein N-terminal acetylation. The NatB complex catalyzes N-acetylation during de novo protein synthesis initiation; however, recent evidence from yeast suggests that NatB also affects post-translational modification of tropomyosin, which is involved in intracellular sorting of aggregated proteins. We hypothesized that an acetylation complex such as NatB may contribute to protein clearance and/or proteostasis in mammalian cells. Using a poly glutamine (polyQ) aggregation system, we examined whether the NatB complex or its components affect protein aggregation in rat primary cultured hippocampal neurons and HEK293 cells. The number of polyQ aggregates increased in Mdm20 over-expressing (OE) cells, but not in Nat5-OE cells. Conversely, in Mdm20 knockdown (KD) cells, but not in Nat5-KD cells, polyQ aggregation was significantly reduced. Although Mdm20 directly associates with Nat5, the overall cellular localization of the two proteins was slightly distinct, and Mdm20 apparently co-localized with the polyQ aggregates. Furthermore, in Mdm20-KD cells, a punctate appearance of LC3 was evident, suggesting the induction of autophagy. Consistent with this notion, phosphorylation of Akt, most notably at Ser473, was greatly reduced in Mdm20-KD cells. These results demonstrate that Mdm20, the so-called auxiliary subunit of the translation-coupled protein N-acetylation complex, contributes to protein clearance and/or aggregate formation by affecting the phosphorylation level of Akt indepenently from the function of Nat5.
authors.affiliation: From the Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: From the Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ohyama
authors.affiliation: From the Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Onga
authors.affiliation: Laboratory of Functional Biology, Kyoto University Graduate School of Biostudies, Kyoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kakizuka
authors.affiliation: From the Department of Anatomy and Neurobiology, Nagasaki University School of Medicine, Nagasaki, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Mori
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D063210:N-Terminal Acetyltransferase B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010455:Peptides; C097188:polyglutamine; D063210:N-Terminal Acetyltransferase B; D051057:Proto-Oncogene Proteins c-akt