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bioRxiv · 10.1101/2021.06.08.447593

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

Hancock-Cerutti, W. F.·Wu, Z.·Tharkeshwar, A. K.·Ferguson, S. M.·Shadel, G. S.·De Camilli, P.
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Abstract

Mutations in VPS13C cause early onset, autosomal recessive Parkinsons Disease (PD). We have established that VPS13C encodes a lipid transfer protein localized to contact sites between the endoplasmic reticulum (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 and place VPS13C in pathways relevant to PD pathogenesis.

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Hancock-Cerutti, W. F., Wu, Z., Tharkeshwar, A. K., Ferguson, S. M., Shadel, G. S., De Camilli, P.. 2021-06-08. ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling. https://doi.org/10.1101/2021.06.08.447593

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