| First Author | Hancock-Cerutti W | Year | 2022 |
| Journal | J Cell Biol | Volume | 221 |
| Issue | 7 | PubMed ID | 35657605 |
| Mgi Jnum | J:336507 | Mgi Id | MGI:7285838 |
| Doi | 10.1083/jcb.202106046 | Citation | Hancock-Cerutti W, et al. (2022) ER-lysosome lipid transfer protein VPS13C/PARK23 prevents aberrant mtDNA-dependent STING signaling. J Cell Biol 221(7):e202106046 |
| abstractText | 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. |
