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Cited by 40Cellular transport and secretionLipid metabolism and biosynthesisProtein Kinase Regulation and GTPase Signaling

Phosphatidylinositol and phosphatidic acid transport between the ER and plasma membrane during PLC activation requires the Nir2 protein

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Kim, Yeun Ju, Guzman-Hernandez, Maria Luisa, Wisniewski, Eva, Echeverria, Nicolas, Balla, Tamas·2016·Biochemical Society Transactions
DOI 10.1042/bst20150187PMC PMC6456894
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Abstract

Phospholipase C (PLC)-mediated hydrolysis of the limited pool of plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] requires replenishment from a larger pool of phosphatidylinositol (PtdIns) via sequential phosphorylation by PtdIns 4-kinases and phosphatidylinositol 4-phosphate (PtdIns4P) 5-kinases. Since PtdIns is synthesized in the endoplasmic reticulum (ER) and PtdIns(4,5)P2 is generated in the PM, it has been postulated that PtdIns transfer proteins (PITPs) provide the means for this lipid transfer function. Recent studies identified the large PITP protein, Nir2 as important for PtdIns transfer from the ER to the PM. It was also found that Nir2 was required for the transfer of phosphatidic acid (PtdOH) from the PM to the ER. In Nir2-depleted cells, activation of PLC leads to PtdOH accumulation in the PM and PtdIns synthesis becomes severely impaired. In quiescent cells, Nir2 is localized to the ER via interaction of its FFAT domain with ER-bound VAMP-associated proteins VAP-A and-B. After PLC activation, Nir2 also binds to the PM via interaction of its C-terminal domains with diacylglycerol (DAG) and PtdOH. Through these interactions, Nir2 functions in ER-PM contact zones. Mutations in VAP-B that have been identified in familial forms of amyotrophic lateral sclerosis (ALS or Lou-Gehrig's disease) cause aggregation of the VAP-B protein, which then impairs its binding to several proteins, including Nir2. These findings have shed new lights on the importance of non-vesicular lipid transfer of PtdIns and PtdOH in ER-PM contact zones with a possible link to a devastating human disease.

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  • Lipid transfer of PI and PA between plasma membrane and ER is accomplished by PITPs.

    “Due to the topological arrangement of the enzymes present in separate membrane compartments (i.e. plasma membrane and ER), lipid transfer of PI and PA has to take place. This is accomplished by a family of PI transfer proteins (PITPs) [23–26].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [26]

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Authors
Kim, Y. J., Guzman-Hernandez, M. L., Wisniewski, E., Echeverria, N., & Balla, T.
Affiliations
  • National Institutes of Health (US)
  • Section on Molecular Signal Transduction, Program for Developmental Neuroscience, Eunice Kennedy Shriver NICHD, National Institutes of Health, Bethesda, MD 20892, U.S.A.
Corresponding author
Echeverria, Nicolas
ORCID
Kim, Yeun Ju
Venue
Biochemical Society Transactions
Publisher
Portland Press Ltd.
Published
2016-02-09
Volume
44
Issue
1
Pages
197-201
ISSN
  • 0300-5127 (ISSN-L)
  • 1470-8752
DOI
10.1042/bst20150187
PMC
PMC6456894
OpenAlex
W2280213866
Cited by
40
References
1
Citations by year
2026: 2 · 2025: 7 · 2024: 4 · 2023: 6 · 2022: 3 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 5
FWCI
0.32
Type
journal article
Language
en
Open access
Locations
  • Biochemical Society Transactions (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (Z01HD000196)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
phosphatidylinositol transfer, phosphatidic acid, phospholipase C activation, endoplasmic reticulum, plasma membrane, VAPA, diacylglycerol, amyotrophic lateral sclerosis, phosphatidylinositol 4,5-bisphosphate
MeSH terms
Animals, Biological Transport, Calcium-Binding Proteins, Cell Membrane, Endoplasmic Reticulum, Humans, Phosphatidic Acids, Phosphatidylinositols, Type C Phospholipases

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