The P5A ATPase Spf1p is stimulated by phosphatidylinositol 4-phosphate and influences cellular sterol homeostasis

Molecular Biology of the Cell
Danny Mollerup SørensenM G Palmgren

Abstract

P5A ATPases are expressed in the endoplasmic reticulum (ER) of all eukaryotic cells, and their disruption results in severe ER stress. However, the function of these ubiquitous membrane proteins, which belong to the P-type ATPase superfamily, is unknown. We purified a functional tagged version of the Saccharomyces cerevisiae P5A ATPase Spf1p and observed that the ATP hydrolytic activity of the protein is stimulated by phosphatidylinositol 4-phosphate (PI4P). Furthermore, SPF1 exhibited negative genetic interactions with SAC1, encoding a PI4P phosphatase, and with OSH1 to OSH6, encoding Osh proteins, which, when energized by a PI4P gradient, drive export of sterols and lipids from the ER. Deletion of SPF1 resulted in increased sensitivity to inhibitors of sterol production, a marked change in the ergosterol/lanosterol ratio, accumulation of sterols in the plasma membrane, and cytosolic accumulation of lipid bodies. We propose that Spf1p maintains cellular sterol homeostasis by influencing the PI4P-induced and Osh-mediated export of sterols from the ER.

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Citations

Oct 12, 2019·NPJ Systems Biology and Applications·Bede P BusbyPaul H Atkinson
Dec 15, 2019·International Journal of Molecular Sciences·Joan Castells-BallesterSabine Strahl
Mar 15, 2020·BMC Biology·Deike J OmnusChristopher J Stefan
Apr 4, 2020·NPJ Systems Biology and Applications·Bede P BusbyPaul H Atkinson
Sep 26, 2020·Science·Michael J McKennaEunyong Park
Apr 7, 2021·Plant Physiology·Rosa L López-MarquésMichael Palmgren
Feb 18, 2021·Molecular Biology of the Cell·Janina LaborenzJohannes M Herrmann
Jun 5, 2021·Biochemical and Biophysical Research Communications·Paula GrenonHugo P Adamo
Jun 21, 2021·Trends in Cell Biology·Verena Dederer, Marius K Lemberg

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Methods Mentioned

BETA
confocal microscopy
fluorescence microscopy
flow cytometry
protein folding
Protein Assay
PCR
acetylation
Assay
dissection

Software Mentioned

Leica LAS AF Lite
Cell Quest
Basic Local Alignment Search Tool ( BLAST )
MaxChelator Webmaxc Extended calculator
Leica
BLAST
RAxML

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