HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels

Petter Holland, Helene Knævelsrud, Kristiane Søreng, Benan J. Mathai, Alf Håkon Lystad, Serhiy Pankiv, Gunnveig T. Bjørndal, Sebastian W. Schultz, Viola H. Lobert, Robin B. Chan, Bowen Zhou, Knut Liestøl, Sven R. Carlsson, Thomas J. Melia, Gilbert Di Paolo and Anne Simonsen ()
Additional contact information
Petter Holland: Institute of Basic Medical Sciences, University of Oslo
Helene Knævelsrud: Institute of Basic Medical Sciences, University of Oslo
Kristiane Søreng: Institute of Basic Medical Sciences, University of Oslo
Benan J. Mathai: Institute of Basic Medical Sciences, University of Oslo
Alf Håkon Lystad: Institute of Basic Medical Sciences, University of Oslo
Serhiy Pankiv: Institute of Basic Medical Sciences, University of Oslo
Gunnveig T. Bjørndal: Institute of Basic Medical Sciences, University of Oslo
Sebastian W. Schultz: Centre for Cancer Biomedicine, Institute for Cancer Research, Oslo University Hospital
Viola H. Lobert: Centre for Cancer Biomedicine, Institute for Cancer Research, Oslo University Hospital
Robin B. Chan: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Bowen Zhou: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Knut Liestøl: Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo
Thomas J. Melia: Yale University School of Medicine
Gilbert Di Paolo: Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center
Anne Simonsen: Institute of Basic Medical Sciences, University of Oslo

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13889

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