The Participation of Regulatory Lipids in Vacuole Homotypic Fusion

In eukaryotes, organelles and vesicles modulate their contents and identities through highly regulated membrane fusion events. Membrane trafficking and fusion are carried out through a series of stages that lead to the formation of SNARE complexes between cellular compartment membranes to trigger fu...

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Bibliographic Details
Published in:Trends in biochemical sciences (Amsterdam. Regular ed.) 2019-06, Vol.44 (6), p.546-554
Main Authors: Starr, Matthew L., Fratti, Rutilio A.
Format: Article
Language:English
Subjects:
Cholesterol - chemistry
Cholesterol - metabolism
Dgk1
Diacylglycerol
Ergosterol - chemistry
Ergosterol - metabolism
Glycerides - chemistry
Glycerides - metabolism
Humans
Lipin1
Membrane Fusion
Pah1
phosphatidic acid
Phosphatidic Acids - chemistry
Phosphatidic Acids - metabolism
Phosphatidylinositols - chemistry
Phosphatidylinositols - metabolism
Sec18
Vacuoles - chemistry
Vacuoles - metabolism
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Summary:In eukaryotes, organelles and vesicles modulate their contents and identities through highly regulated membrane fusion events. Membrane trafficking and fusion are carried out through a series of stages that lead to the formation of SNARE complexes between cellular compartment membranes to trigger fusion. Although the protein catalysts of membrane fusion are well characterized, their response to their surrounding microenvironment, provided by the lipid composition of the membrane, remains to be fully understood. Membranes are composed of bulk lipids (e.g., phosphatidylcholine), as well as regulatory lipids that undergo constant modifications by kinases, phosphatases, and lipases. These lipids include phosphoinositides, diacylglycerol, phosphatidic acid, and cholesterol/ergosterol. Here we describe the roles of these lipids throughout the stages of yeast vacuole homotypic fusion. Vacuole fusion is spatiotemporally controlled by regulatory lipids and their modifications. The phosphatidic acid (PA) phosphatase Pah1/Lipin1 regulates vacuole maturation by affecting the recruitment of the phosphatidylinositol (PI) 3-kinase Vps34 and its production of PI 3-phosphate (PI3P). PI3P recruits the nucleotide exchange factor Mon1–Ccz1, which then recruits and activates the Rab Ypt7. PA sequesters Sec18 protomers from cis-SNARE complexes to prevent priming. The conversion of PA to diacylglycerol (DAG) by Pah1 releases Sec18 from the membrane to allow SNARE priming. The soluble Qc-SNARE Vam7 contains a polybasic region (PBR) in its middle domain that regulates the PI3P binding of the adjacent PX domain as part of an autoregulatory mechanism. The DAG kinase Dgk1 converts DAG to PA and its deletion augments vacuole fusion. The increase in fusion is linked to enhanced Ypt7 activity in the presence of elevated DAG concentrations.
ISSN:0968-0004
1362-4326
DOI:10.1016/j.tibs.2018.12.003