ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling.
Journal
The Journal of cell biology
ISSN: 1540-8140
Titre abrégé: J Cell Biol
Pays: United States
ID NLM: 0375356
Informations de publication
Date de publication:
04 07 2022
04 07 2022
Historique:
received:
08
06
2021
accepted:
03
05
2022
entrez:
3
6
2022
pubmed:
4
6
2022
medline:
9
6
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35657605
pii: 213259
doi: 10.1083/jcb.202106046
pmc: PMC9170524
pii:
doi:
Substances chimiques
DNA, Mitochondrial
0
Lipids
0
Membrane Proteins
0
Proteins
0
STING1 protein, human
0
VPS13C protein, human
0
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Chan Zuckerberg Initiative
ID : 2020-221912
Organisme : Michael J. Fox Foundation for Parkinson's Research
ID : ASAP-000580
Organisme : China Scholarship Counsel
Organisme : Aligning Science Across Parkinson's
Organisme : American Heart Association
Organisme : NIDA NIH HHS
ID : P30 DA018343
Pays : United States
Organisme : Parkinson Foundation
ID : PF-RCE-1946
Organisme : NIDDK NIH HHS
ID : P30 DK045735
Pays : United States
Organisme : Audrey Geisel Chair in Biomedical Science
Organisme : NIH HHS
ID : NS36251
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR069876
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007205
Pays : United States
Organisme : Allen Initiative in Brain Health and Cognitive Impairment award
ID : 19PABH134610000
Informations de copyright
© 2022 Hancock-Cerutti et al.
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