Receptor-mediated endocytosis 8 (RME-8)/DNAJC13 is a novel positive modulator of autophagy and stabilizes cellular protein homeostasis
| Autor: | Luise Florin, Joanna Maus, Karsten Nalbach, Heike Huesmann, Ines F Pfalzgraf, Christian Behl, Stella Vo, Anna Stein, Anna S. Besemer, Christian M. von Hilchen, Mirjam D A Ax, Beate Silva, Fatima Boukhallouk, Andreas Kern, Christian Freese, Ingrid Koziollek-Drechsler, Albrecht M. Clement |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
540 Chemistry and allied sciences
Retromer Endosome 610 Medizin Cellular homeostasis Endocytosis 570 Life sciences 03 medical and health sciences Cellular and Molecular Neuroscience Protein Aggregates 0302 clinical medicine 610 Medical sciences Autophagy Animals Humans ATG9A Caenorhabditis elegans Caenorhabditis elegans Proteins Molecular Biology 030304 developmental biology Pharmacology 0303 health sciences Gene knockdown DNAJC13 Chemistry Cell Biology Receptor-mediated endocytosis Cell biology Proteostasis HEK293 Cells 540 Chemie C. elegans Molecular Medicine Original Article RME-8 Recycling endosome 030217 neurology & neurosurgery 570 Biowissenschaften HeLa Cells Molecular Chaperones |
| Zdroj: | Cellular and Molecular Life Sciences |
| ISSN: | 1420-9071 1420-682X |
| Popis: | The cellular protein homeostasis (proteostasis) network responds effectively to insults. In a functional screen in C. elegans, we recently identified the gene receptor-mediated endocytosis 8 (rme-8; human ortholog: DNAJC13) as a component of the proteostasis network. Accumulation of aggregation-prone proteins, such as amyloid-β 42 (Aβ), α-synuclein, or mutant Cu/Zn-superoxide dismutase (SOD1), were aggravated upon the knockdown of rme-8/DNAJC13 in C. elegans and in human cell lines, respectively. DNAJC13 is involved in endosomal protein trafficking and associated with the retromer and the WASH complex. As both complexes have been linked to autophagy, we investigated the role of DNAJC13 in this degradative pathway. In knockdown and overexpression experiments, DNAJC13 acts as a positive modulator of autophagy. In contrast, the overexpression of the Parkinson’s disease-associated mutant DNAJC13(N855S) did not enhance autophagy. Reduced DNAJC13 levels affected ATG9A localization at and its transport from the recycling endosome. As a consequence, ATG9A co-localization at LC3B-positive puncta under steady-state and autophagy-induced conditions is impaired. These data demonstrate a novel function of RME-8/DNAJC13 in cellular homeostasis by modulating ATG9A trafficking and autophagy. |
| Databáze: | OpenAIRE |
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