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ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling

Mutations in VPS13C cause early-onset, autosomal recessive Parkinson’s disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells cause...

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Autores principales: Hancock-Cerutti, William, Wu, Zheng, Xu, Peng, Yadavalli, Narayana, Leonzino, Marianna, Tharkeshwar, Arun Kumar, Ferguson, Shawn M., Shadel, Gerald S., De Camilli, Pietro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170524/
https://www.ncbi.nlm.nih.gov/pubmed/35657605
http://dx.doi.org/10.1083/jcb.202106046
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author Hancock-Cerutti, William
Wu, Zheng
Xu, Peng
Yadavalli, Narayana
Leonzino, Marianna
Tharkeshwar, Arun Kumar
Ferguson, Shawn M.
Shadel, Gerald S.
De Camilli, Pietro
author_facet Hancock-Cerutti, William
Wu, Zheng
Xu, Peng
Yadavalli, Narayana
Leonzino, Marianna
Tharkeshwar, Arun Kumar
Ferguson, Shawn M.
Shadel, Gerald S.
De Camilli, Pietro
author_sort Hancock-Cerutti, William
collection PubMed
description Mutations in VPS13C cause early-onset, autosomal recessive Parkinson’s disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS-STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation in a model human cell line and place VPS13C in pathways relevant to PD pathogenesis.
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spelling pubmed-91705242022-06-07 ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling Hancock-Cerutti, William Wu, Zheng Xu, Peng Yadavalli, Narayana Leonzino, Marianna Tharkeshwar, Arun Kumar Ferguson, Shawn M. Shadel, Gerald S. De Camilli, Pietro J Cell Biol Article Mutations in VPS13C cause early-onset, autosomal recessive Parkinson’s disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the ER and late endosomes/lysosomes. In the current study, we demonstrate that depleting VPS13C in HeLa cells causes an accumulation of lysosomes with an altered lipid profile, including an accumulation of di-22:6-BMP, a biomarker of the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation. In addition, the DNA-sensing cGAS-STING pathway, which was recently implicated in PD pathogenesis, is activated in these cells. This activation results from a combination of elevated mitochondrial DNA in the cytosol and a defect in the degradation of activated STING, a lysosome-dependent process. These results suggest a link between ER-lysosome lipid transfer and innate immune activation in a model human cell line and place VPS13C in pathways relevant to PD pathogenesis. Rockefeller University Press 2022-06-03 /pmc/articles/PMC9170524/ /pubmed/35657605 http://dx.doi.org/10.1083/jcb.202106046 Text en © 2022 Hancock-Cerutti et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hancock-Cerutti, William
Wu, Zheng
Xu, Peng
Yadavalli, Narayana
Leonzino, Marianna
Tharkeshwar, Arun Kumar
Ferguson, Shawn M.
Shadel, Gerald S.
De Camilli, Pietro
ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling
title ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling
title_full ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling
title_fullStr ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling
title_full_unstemmed ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling
title_short ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling
title_sort er-lysosome lipid transfer protein vps13c/park23 prevents aberrant mtdna-dependent sting signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9170524/
https://www.ncbi.nlm.nih.gov/pubmed/35657605
http://dx.doi.org/10.1083/jcb.202106046
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