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.; Camilli, Pietro De

doi:10.1083/jcb.202106046

Cited by 53 publications

(56 citation statements)

References 82 publications

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“…The ER is relatively enriched in those lipid species compared to endo-lysosomes (Escribá et al, 2015; Guo et al, 2009; Horvath and Daum, 2013; Pogozheva et al, 2022; Reglinski et al, 2020; Tauchi-Sato et al, 2002; van Meer and de Kroon, 2011; van Meer et al, 2008). Despite this, the levels of phosphatidylcholine, phosphatidylserine, phosphatidylinositol, and sphingomyelin increase in the lysosome in VPS13C knockout clones (Hancock-Cerutti et al, 2022). Intriguingly, this suggests that VPS13C-mediated lipid transfer can be compensated for by other mechanisms.…”

Section: Discussionmentioning

confidence: 99%

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In silico modelling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms

Armellina

Stagi

Swan

2022

Preprint

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The VPS13 protein family constitutes a novel class of bridge-like lipid transferases. Autosomal recessive inheritance of mutations in VPS13 genes is associated with the development of neurodegenerative diseases in humans. Bioinformatic approaches previously recognised the domain architecture of these proteins. In this study, we model the first ever full-length structures of the four human homologs VPS13A, VPS13B, VPS13C, and VPS13D in association with model membranes, to investigate their lipid transfer ability and potential structural association with membrane leaflets. We analyse the evolutionary conservation and physicochemical properties of these proteins, focusing on conserved C-terminal amphipathic helices that disturb organelle surfaces and that, adjoined, resemble a traditional Venetian gondola. The gondola domains share significant structural homology with lipid droplet surface-binding proteins. We introduce in silico protein-membrane models displaying the mode of association of VPS13A, VPS13B, VPS13C, and VPS13D to donor and target membranes, and present potential models of action for protein-mediated lipid transfer.

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Section: Discussionmentioning

confidence: 99%

“…VPS13C also localises at ER-lipid droplet, at ER-endo-lysosome jucntions (Kumar et al, 2018). Here, it is thought to interact with the GTPase Rab7 (McCray et al, 2010, Hancock-Cerutti et al 2022). Tethered at Golgi-endosome contact sites are VPS13B proteins (Seifert et al, 2011), which were shown to bind Rab6 (Seifert et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

In silico modelling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms

Armellina

Stagi

Swan

2022

Preprint

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“…Using a CRISPR-iPSC-based approach, a group generated VPS13C knockout iPSC-derived neuronal cell lines in which they studied knockout-mediated lysosomal function alteration. Combining these insights with that derived from VPS13C knockout HeLa cells and VPS13C −/− mice, the group demonstrated the perturbation of lysosomal lipid homeostasis in VPS13C -deficient cells, thereby suggesting the involvement of VPS13C in PD pathogenesis-relevant pathways (Hancock-Cerutti et al 2022 ).…”

Section: Parkinson’s Diseasementioning

confidence: 96%

CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics

Sen

Thummer

2022

Neurotox Res

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Neurodegenerative diseases are prominent causes of pain, suffering, and death worldwide. Traditional approaches modelling neurodegenerative diseases are deficient, and therefore, improved strategies that effectively recapitulate the pathophysiological conditions of neurodegenerative diseases are the need of the hour. The generation of human-induced pluripotent stem cells (iPSCs) has transformed our ability to model neurodegenerative diseases in vitro and provide an unlimited source of cells (including desired neuronal cell types) for cell replacement therapy. Recently, CRISPR/Cas9-based genome editing has also been gaining popularity because of the flexibility they provide to generate and ablate disease phenotypes. In addition, the recent advancements in CRISPR/Cas9 technology enables researchers to seamlessly target and introduce precise modifications in the genomic DNA of different human cell lines, including iPSCs. CRISPR-iPSC-based disease modelling, therefore, allows scientists to recapitulate the pathological aspects of most neurodegenerative processes and investigate the role of pathological gene variants in healthy non-patient cell lines. This review outlines how iPSCs, CRISPR/Cas9, and CRISPR-iPSC-based approaches accelerate research on neurodegenerative diseases and take us closer to a cure for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Amyotrophic Lateral Sclerosis, and so forth.

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“…Defective mitochondrial membrane structure and increased permeability are key causes of mtDNA leakage. Altered lipid composition in the mitochondrial membrane leads to increased mitochondrial permeability and mtDNA leakage [ 31 ]. Mitochondrial damage caused by multiple factors is often accompanied by mtDNA leakage.…”

Section: Common Types Of Mtdna Damagementioning

confidence: 99%

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

Feng

Chen

Liang

et al. 2022

IJMS

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The kidney is a mitochondria-rich organ, and kidney diseases are recognized as mitochondria-related pathologies. Intact mitochondrial DNA (mtDNA) maintains normal mitochondrial function. Mitochondrial dysfunction caused by mtDNA damage, including impaired mtDNA replication, mtDNA mutation, mtDNA leakage, and mtDNA methylation, is involved in the progression of kidney diseases. Herein, we review the roles of mtDNA damage in different setting of kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD). In a variety of kidney diseases, mtDNA damage is closely associated with loss of kidney function. The level of mtDNA in peripheral serum and urine also reflects the status of kidney injury. Alleviating mtDNA damage can promote the recovery of mitochondrial function by exogenous drug treatment and thus reduce kidney injury. In short, we conclude that mtDNA damage may serve as a novel biomarker for assessing kidney injury in different causes of renal dysfunction, which provides a new theoretical basis for mtDNA-targeted intervention as a therapeutic option for kidney diseases.

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

Cited by 53 publications

References 82 publications

In silico modelling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms

In silico modelling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms

CRISPR and iPSCs: Recent Developments and Future Perspectives in Neurodegenerative Disease Modelling, Research, and Therapeutics

Roles of Mitochondrial DNA Damage in Kidney Diseases: A New Biomarker

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