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The NTPase activity of the double FYVE domain–containing protein 1 regulates lipid droplet metabolism
Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks and therefore play a central role in cellular metabolism. However, the molecular factors and underlying mechanisms that regulate the growth and degradation of...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9881219/ https://www.ncbi.nlm.nih.gov/pubmed/36574842 http://dx.doi.org/10.1016/j.jbc.2022.102830 |
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author | Ismail, V.A. Naismith, T. Kast, D.J. |
author_facet | Ismail, V.A. Naismith, T. Kast, D.J. |
author_sort | Ismail, V.A. |
collection | PubMed |
description | Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks and therefore play a central role in cellular metabolism. However, the molecular factors and underlying mechanisms that regulate the growth and degradation of LDs are poorly understood. It has emerged that proteins that establish contacts between LDs and the endoplasmic reticulum play a critical role in regulating LD metabolism. Recently, the autophagy-related protein, double FYVE domain–containing protein 1 (DFCP1/ZFYVE1) was shown to reside at the interface of the endoplasmic reticulum and LDs, however, little is known about the involvement of DFCP1 in autophagy and LD metabolism. Here, we show that DFCP1 is a novel NTPase that regulates free fatty acid metabolism. Specifically, we show that DFPC1-knockdown, particularly during starvation, increases cellular free fatty acids and decreases the levels of cellular TAGs, resulting in accumulated small LDs. Using selective truncations, we demonstrate that DFCP1 accumulation on LDs in cells and in vitro is regulated by a previously unknown NTPase domain. Using spectroscopic approaches, we show that this NTPase domain can dimerize and can hydrolyze both ATP and GTP. Furthermore, mutations in DFCP1 that either impact nucleotide hydrolysis or dimerization result in changes in the accumulation of DFCP1 on LDs, changes in LD density and size, and colocalization of LDs to autophagosomes. Collectively, our findings suggest that DFCP1 is an NTPase that modulates the metabolism of LDs in cells. |
format | Online Article Text |
id | pubmed-9881219 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-98812192023-01-31 The NTPase activity of the double FYVE domain–containing protein 1 regulates lipid droplet metabolism Ismail, V.A. Naismith, T. Kast, D.J. J Biol Chem Research Article Lipid droplets (LDs) are transient lipid storage organelles that can be readily tapped to resupply cells with energy or lipid building blocks and therefore play a central role in cellular metabolism. However, the molecular factors and underlying mechanisms that regulate the growth and degradation of LDs are poorly understood. It has emerged that proteins that establish contacts between LDs and the endoplasmic reticulum play a critical role in regulating LD metabolism. Recently, the autophagy-related protein, double FYVE domain–containing protein 1 (DFCP1/ZFYVE1) was shown to reside at the interface of the endoplasmic reticulum and LDs, however, little is known about the involvement of DFCP1 in autophagy and LD metabolism. Here, we show that DFCP1 is a novel NTPase that regulates free fatty acid metabolism. Specifically, we show that DFPC1-knockdown, particularly during starvation, increases cellular free fatty acids and decreases the levels of cellular TAGs, resulting in accumulated small LDs. Using selective truncations, we demonstrate that DFCP1 accumulation on LDs in cells and in vitro is regulated by a previously unknown NTPase domain. Using spectroscopic approaches, we show that this NTPase domain can dimerize and can hydrolyze both ATP and GTP. Furthermore, mutations in DFCP1 that either impact nucleotide hydrolysis or dimerization result in changes in the accumulation of DFCP1 on LDs, changes in LD density and size, and colocalization of LDs to autophagosomes. Collectively, our findings suggest that DFCP1 is an NTPase that modulates the metabolism of LDs in cells. American Society for Biochemistry and Molecular Biology 2022-12-24 /pmc/articles/PMC9881219/ /pubmed/36574842 http://dx.doi.org/10.1016/j.jbc.2022.102830 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Ismail, V.A. Naismith, T. Kast, D.J. The NTPase activity of the double FYVE domain–containing protein 1 regulates lipid droplet metabolism |
title | The NTPase activity of the double FYVE domain–containing protein 1 regulates lipid droplet metabolism |
title_full | The NTPase activity of the double FYVE domain–containing protein 1 regulates lipid droplet metabolism |
title_fullStr | The NTPase activity of the double FYVE domain–containing protein 1 regulates lipid droplet metabolism |
title_full_unstemmed | The NTPase activity of the double FYVE domain–containing protein 1 regulates lipid droplet metabolism |
title_short | The NTPase activity of the double FYVE domain–containing protein 1 regulates lipid droplet metabolism |
title_sort | ntpase activity of the double fyve domain–containing protein 1 regulates lipid droplet metabolism |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9881219/ https://www.ncbi.nlm.nih.gov/pubmed/36574842 http://dx.doi.org/10.1016/j.jbc.2022.102830 |
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