PMID- 36823305
OWN - NLM
STAT- MEDLINE
DCOM- 20230227
LR  - 20240426
IS  - 2399-3642 (Electronic)
IS  - 2399-3642 (Linking)
VI  - 6
IP  - 1
DP  - 2023 Feb 23
TI  - Lysosomal phospholipase A2 contributes to the biosynthesis of the atypical late 
      endosome lipid bis(monoacylglycero)phosphate.
PG  - 210
LID - 10.1038/s42003-023-04573-z [doi]
LID - 210
AB  - The late endosome/lysosome (LE/Lys) lipid bis(monoacylglycero)phosphate (BMP) 
      plays major roles in cargo sorting and degradation, regulation of cholesterol and 
      intercellular communication and has been linked to viral infection and 
      neurodegeneration. Although BMP was initially described over fifty years ago, the 
      enzymes regulating its synthesis remain unknown. The first step in the BMP 
      biosynthetic pathway is the conversion of phosphatidylglycerol (PG) into 
      lysophosphatidylglycerol (LPG) by a phospholipase A2 (PLA2) enzyme. Here we 
      report that this enzyme is lysosomal PLA2 (LPLA2). We show that LPLA2 is 
      sufficient to convert PG into LPG in vitro. We show that modulating LPLA2 levels 
      regulates BMP levels in HeLa cells, and affects downstream pathways such as 
      LE/Lys morphology and cholesterol levels. Finally, we show that in a model of 
      Niemann-Pick disease type C, overexpressing LPLA2 alleviates the LE/Lys 
      cholesterol accumulation phenotype. Altogether, we shed new light on BMP 
      biosynthesis and contribute tools to regulate BMP-dependent pathways.
CI  - (c) 2023. The Author(s).
FAU - Chen, Jacinda
AU  - Chen J
AD  - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia 
      University Irving Medical Center, New York City, NY, 10032, USA.
FAU - Cazenave-Gassiot, Amaury
AU  - Cazenave-Gassiot A
AUID- ORCID: 0000-0002-3050-634X
AD  - Department of Biochemistry and Precision Medicine Translational Research Program, 
      Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 
      117597, Singapore.
AD  - Singapore Lipidomics Incubator, Life Sciences Institute, National University of 
      Singapore, Singapore, 117456, Singapore.
FAU - Xu, Yimeng
AU  - Xu Y
AD  - Biomarkers Core Laboratory, Irving Institute for Clinical and Translational 
      Research, Columbia University Irving Medical Center, New York City, NY, 10032, 
      USA.
FAU - Piroli, Paola
AU  - Piroli P
AD  - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia 
      University Irving Medical Center, New York City, NY, 10032, USA.
FAU - Hwang, Robert Jr
AU  - Hwang R Jr
AD  - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia 
      University Irving Medical Center, New York City, NY, 10032, USA.
FAU - DeFreitas, Laura
AU  - DeFreitas L
AD  - Biomarkers Core Laboratory, Irving Institute for Clinical and Translational 
      Research, Columbia University Irving Medical Center, New York City, NY, 10032, 
      USA.
FAU - Chan, Robin Barry
AU  - Chan RB
AD  - Department of Pathology and Cell Biology, Columbia University Irving Medical 
      Center, New York City, NY, 10032, USA.
AD  - AliveX Biotech, Shanghai, China.
FAU - Di Paolo, Gilbert
AU  - Di Paolo G
AUID- ORCID: 0000-0003-1032-1265
AD  - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia 
      University Irving Medical Center, New York City, NY, 10032, USA.
AD  - Department of Pathology and Cell Biology, Columbia University Irving Medical 
      Center, New York City, NY, 10032, USA.
AD  - Denali Therapeutics Inc., South San Francisco, CA, USA.
FAU - Nandakumar, Renu
AU  - Nandakumar R
AD  - Biomarkers Core Laboratory, Irving Institute for Clinical and Translational 
      Research, Columbia University Irving Medical Center, New York City, NY, 10032, 
      USA.
FAU - Wenk, Markus R
AU  - Wenk MR
AD  - Department of Biochemistry and Precision Medicine Translational Research Program, 
      Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 
      117597, Singapore.
AD  - Singapore Lipidomics Incubator, Life Sciences Institute, National University of 
      Singapore, Singapore, 117456, Singapore.
FAU - Marquer, Catherine
AU  - Marquer C
AUID- ORCID: 0000-0002-4064-9213
AD  - Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia 
      University Irving Medical Center, New York City, NY, 10032, USA. 
      cm3244@cumc.columbia.edu.
AD  - Department of Pathology and Cell Biology, Columbia University Irving Medical 
      Center, New York City, NY, 10032, USA. cm3244@cumc.columbia.edu.
LA  - eng
GR  - R03 AG078682/AG/NIA NIH HHS/United States
GR  - R21 AG056758/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230223
PL  - England
TA  - Commun Biol
JT  - Communications biology
JID - 101719179
RN  - 0 (bis(monoacylglyceryl)phosphate)
RN  - EC 3.1.1.4 (Phospholipases A2)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Humans
MH  - HeLa Cells
MH  - Phospholipases A2/metabolism
MH  - *Endosomes/metabolism
MH  - *Lysosomes/metabolism
MH  - Cholesterol/metabolism
PMC - PMC9950130
COIS- R.B.C. is a current employee and shareholder of AliveX Biotech. G.D.P. is a 
      current employee and shareholder of Denali Therapeutics Inc. The other authors 
      declare no competing financial interests.
EDAT- 2023/02/25 06:00
MHDA- 2023/03/03 06:00
PMCR- 2023/02/23
CRDT- 2023/02/24 00:06
PHST- 2022/07/06 00:00 [received]
PHST- 2023/02/09 00:00 [accepted]
PHST- 2023/02/24 00:06 [entrez]
PHST- 2023/02/25 06:00 [pubmed]
PHST- 2023/03/03 06:00 [medline]
PHST- 2023/02/23 00:00 [pmc-release]
AID - 10.1038/s42003-023-04573-z [pii]
AID - 4573 [pii]
AID - 10.1038/s42003-023-04573-z [doi]
PST - epublish
SO  - Commun Biol. 2023 Feb 23;6(1):210. doi: 10.1038/s42003-023-04573-z.