HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels
| Autor: | Gilbert Di Paolo, Kristiane Søreng, Serhiy Pankiv, Anne Simonsen, Petter Holland, Viola Hélène Lobert, Knut Liestøl, Bowen Zhou, Benan John Mathai, Helene Knævelsrud, Thomas J. Melia, Gunnveig Toft Bjørndal, Robin B. Chan, Sebastian W. Schultz, Alf Håkon Lystad, Sven R. Carlsson |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Science Cell- och molekylärbiologi education Protein domain Autophagy-Related Proteins Phosphatidic Acids General Physics and Astronomy Nerve Tissue Proteins Models Biological Article General Biochemistry Genetics and Molecular Biology Cell Line Animals Genetically Modified Membrane Lipids 03 medical and health sciences chemistry.chemical_compound Protein Domains Autophagy Phospholipase D Animals Humans Zebrafish Multidisciplinary biology HEK 293 cells Autophagosomes General Chemistry PX domain Phosphatidic acid Zebrafish Proteins biology.organism_classification Cell biology HS1BP3 HEK293 Cells 030104 developmental biology chemistry Cell culture Cortactin Cell and Molecular Biology HeLa Cells |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-13 (2016) |
| ISSN: | 2041-1723 |
| Popis: | A fundamental question is how autophagosome formation is regulated. Here we show that the PX domain protein HS1BP3 is a negative regulator of autophagosome formation. HS1BP3 depletion increased the formation of LC3-positive autophagosomes and degradation of cargo both in human cell culture and in zebrafish. HS1BP3 is localized to ATG16L1- and ATG9-positive autophagosome precursors and we show that HS1BP3 binds phosphatidic acid (PA) through its PX domain. Furthermore, we find the total PA content of cells to be significantly upregulated in the absence of HS1BP3, as a result of increased activity of the PA-producing enzyme phospholipase D (PLD) and increased localization of PLD1 to ATG16L1-positive membranes. We propose that HS1BP3 regulates autophagy by modulating the PA content of the ATG16L1-positive autophagosome precursor membranes through PLD1 activity and localization. Our findings provide key insights into how autophagosome formation is regulated by a novel negative-feedback mechanism on membrane lipids. Autophagy must be tightly controlled at each step of the process. Here the authors show that HS1BP3 binds phosphatidic acid (PA) at autophagosome precursors and negatively regulates autophagosome formation by modulating the activity and localization of the PA-producing enzyme phospholipase D1. |
| Databáze: | OpenAIRE |
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