Cargando…
A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane
Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally shaped erythrocytes. XK belongs to a family of...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436381/ https://www.ncbi.nlm.nih.gov/pubmed/35994651 http://dx.doi.org/10.1073/pnas.2205425119 |
_version_ | 1784781350535954432 |
---|---|
author | Guillén-Samander, Andrés Wu, Yumei Pineda, S. Sebastian García, Francisco J. Eisen, Julia N. Leonzino, Marianna Ugur, Berrak Kellis, Manolis Heiman, Myriam De Camilli, Pietro |
author_facet | Guillén-Samander, Andrés Wu, Yumei Pineda, S. Sebastian García, Francisco J. Eisen, Julia N. Leonzino, Marianna Ugur, Berrak Kellis, Manolis Heiman, Myriam De Camilli, Pietro |
author_sort | Guillén-Samander, Andrés |
collection | PubMed |
description | Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally shaped erythrocytes. XK belongs to a family of plasma membrane (PM) lipid scramblases whose action results in exposure of PtdSer at the cell surface. VPS13A is an endoplasmic reticulum (ER)-anchored lipid transfer protein with a putative role in the transport of lipids at contacts of the ER with other membranes. Recently VPS13A and XK were reported to interact by still unknown mechanisms. So far, however, there is no evidence for a colocalization of the two proteins at contacts of the ER with the PM, where XK resides, as VPS13A was shown to be localized at contacts between the ER and either mitochondria or lipid droplets. Here we show that VPS13A can also localize at ER–PM contacts via the binding of its PH domain to a cytosolic loop of XK, that such interaction is regulated by an intramolecular interaction within XK, and that both VPS13A and XK are highly expressed in the caudate neurons. Binding of the PH domain of VPS13A to XK is competitive with its binding to intracellular membranes that mediate other tethering functions of VPS13A. Our findings support a model according to which VPS13A-dependent lipid transfer between the ER and the PM is coupled to lipid scrambling within the PM. They raise the possibility that defective cell surface exposure of PtdSer may be responsible for neurodegeneration. |
format | Online Article Text |
id | pubmed-9436381 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-94363812022-09-02 A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane Guillén-Samander, Andrés Wu, Yumei Pineda, S. Sebastian García, Francisco J. Eisen, Julia N. Leonzino, Marianna Ugur, Berrak Kellis, Manolis Heiman, Myriam De Camilli, Pietro Proc Natl Acad Sci U S A Biological Sciences Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally shaped erythrocytes. XK belongs to a family of plasma membrane (PM) lipid scramblases whose action results in exposure of PtdSer at the cell surface. VPS13A is an endoplasmic reticulum (ER)-anchored lipid transfer protein with a putative role in the transport of lipids at contacts of the ER with other membranes. Recently VPS13A and XK were reported to interact by still unknown mechanisms. So far, however, there is no evidence for a colocalization of the two proteins at contacts of the ER with the PM, where XK resides, as VPS13A was shown to be localized at contacts between the ER and either mitochondria or lipid droplets. Here we show that VPS13A can also localize at ER–PM contacts via the binding of its PH domain to a cytosolic loop of XK, that such interaction is regulated by an intramolecular interaction within XK, and that both VPS13A and XK are highly expressed in the caudate neurons. Binding of the PH domain of VPS13A to XK is competitive with its binding to intracellular membranes that mediate other tethering functions of VPS13A. Our findings support a model according to which VPS13A-dependent lipid transfer between the ER and the PM is coupled to lipid scrambling within the PM. They raise the possibility that defective cell surface exposure of PtdSer may be responsible for neurodegeneration. National Academy of Sciences 2022-08-22 2022-08-30 /pmc/articles/PMC9436381/ /pubmed/35994651 http://dx.doi.org/10.1073/pnas.2205425119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Guillén-Samander, Andrés Wu, Yumei Pineda, S. Sebastian García, Francisco J. Eisen, Julia N. Leonzino, Marianna Ugur, Berrak Kellis, Manolis Heiman, Myriam De Camilli, Pietro A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
title | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
title_full | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
title_fullStr | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
title_full_unstemmed | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
title_short | A partnership between the lipid scramblase XK and the lipid transfer protein VPS13A at the plasma membrane |
title_sort | partnership between the lipid scramblase xk and the lipid transfer protein vps13a at the plasma membrane |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9436381/ https://www.ncbi.nlm.nih.gov/pubmed/35994651 http://dx.doi.org/10.1073/pnas.2205425119 |
work_keys_str_mv | AT guillensamanderandres apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT wuyumei apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT pinedassebastian apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT garciafranciscoj apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT eisenjulian apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT leonzinomarianna apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT ugurberrak apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT kellismanolis apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT heimanmyriam apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT decamillipietro apartnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT guillensamanderandres partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT wuyumei partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT pinedassebastian partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT garciafranciscoj partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT eisenjulian partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT leonzinomarianna partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT ugurberrak partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT kellismanolis partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT heimanmyriam partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane AT decamillipietro partnershipbetweenthelipidscramblasexkandthelipidtransferproteinvps13aattheplasmamembrane |