α/β Hydrolase Domain-containing 6 (ABHD6) Degrades the Late Endosomal/Lysosomal Lipid Bis(monoacylglycero)phosphate.
α/β Hydrolase domain-containing 6 (ABHD6) can act as monoacylglycerol hydrolase and is believed to play a role in endocannabinoid signaling as well as in the pathogenesis of obesity and liver steatosis. However, the mechanistic link between gene function and disease is incompletely understood. Here we aimed to further characterize the role of ABHD6 in lipid metabolism. We show that mouse and human ABHD6 degrade bis(monoacylglycero)phosphate (BMP) with high specific activity. BMP, also known as lysobisphosphatidic acid, is enriched in late endosomes/lysosomes, where it plays a key role in the formation of intraluminal vesicles and in lipid sorting. Up to now, little has been known about the catabolism of this lipid. Our data demonstrate that ABHD6 is responsible for ∼ 90% of the BMP hydrolase activity detected in the liver and that knockdown of ABHD6 increases hepatic BMP levels. Tissue fractionation and live-cell imaging experiments revealed that ABHD6 co-localizes with late endosomes/lysosomes. The enzyme is active at cytosolic pH and lacks acid hydrolase activity, implying that it degrades BMP exported from acidic organelles or de novo-formed BMP. In conclusion, our data suggest that ABHD6 controls BMP catabolism and is therefore part of the late endosomal/lysosomal lipid-sorting machinery.
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Maria A
MA
Pribasnig
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Irina
I
Mrak
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Gernot F
GF
Grabner
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Ulrike
U
Taschler
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Oskar
O
Knittelfelder
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Barbara
B
Scherz
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Thomas O
TO
Eichmann
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Christoph
C
Heier
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Lukas
L
Grumet
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Jakob
J
Kowaliuk
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Matthias
M
Romauch
the University of Technology, 8010 Graz, Austria.
Stefan
S
Holler
the University of Technology, 8010 Graz, Austria.
Felix
F
Anderl
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Heimo
H
Wolinski
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Achim
A
Lass
the University of Technology, 8010 Graz, Austria.
Rolf
R
Breinbauer
the Institute of Organic Chemistry, Medical University of Graz, 8010 Graz, Austria, and.
Gunther
G
Marsche
the Institute of Experimental and Clinical Pharmacology, Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio 44195.
J Mark
JM
Brown
From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria, robert.zimmermann@uni-graz.at.
Robert
R
Zimmermann
D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D008246:Lysophospholipids / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008994:Monoacylglycerol Lipases / Q000378:metabolism*; D050178:Monoglycerides / Q000378:metabolism*
D008246:Lysophospholipids; D050178:Monoglycerides; C012786:bis(monoacylglyceryl)phosphate; C540878:ABHD6 protein, human; D008994:Monoacylglycerol Lipases
bis(monoacylglycero)phosphate; endocannabinoid; endosome; lipid metabolism; lysobisphosphatidic acid; lysosome; phospholipase