Mdm20 Stimulates PolyQ Aggregation via Inhibiting Autophagy Through Akt-Ser473 PhosphorylationReportar como inadecuado

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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.

Autor: Kunihiko Yasuda, Kyoji Ohyama, Kazuko Onga, Akira Kakizuka, Nozomu Mori



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