AI Article Synopsis
Article Abstract
Cholesterol accumulation in late endosomes is a prevailing phenotype of Niemann-Pick type C1 (NPC1) mutant cells. Likewise, annexin A6 (AnxA6) overexpression induces a phenotype reminiscent of NPC1 mutant cells. Here, we demonstrate that this cellular cholesterol imbalance is due to AnxA6 promoting Rab7 inactivation via TBC1D15, a Rab7-GAP. In NPC1 mutant cells, AnxA6 depletion and eventual Rab7 activation was associated with peripheral distribution and increased mobility of late endosomes. This was accompanied by an enhanced lipid accumulation in lipid droplets in an acyl-CoA:cholesterol acyltransferase (ACAT)-dependent manner. Moreover, in AnxA6-deficient NPC1 mutant cells, Rab7-mediated rescue of late endosome-cholesterol export required the StAR-related lipid transfer domain-3 (StARD3) protein. Electron microscopy revealed a significant increase of membrane contact sites (MCS) between late endosomes and ER in NPC1 mutant cells lacking AnxA6, suggesting late endosome-cholesterol transfer to the ER via Rab7 and StARD3-dependent MCS formation. This study identifies AnxA6 as a novel gatekeeper that controls cellular distribution of late endosome-cholesterol via regulation of a Rab7-GAP and MCS formation.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326902 | PMC |
| http://dx.doi.org/10.1007/s00018-019-03330-y | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Global cellular proteo-lipidomic profiling of diverse lysosomal storage disease mutants using nMOST.
Sci Adv
January 2025
Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Lysosomal storage diseases (LSDs) comprise ~50 monogenic disorders marked by the buildup of cellular material in lysosomes, yet systematic global molecular phenotyping of proteins and lipids is lacking. We present a nanoflow-based multiomic single-shot technology (nMOST) workflow that quantifies HeLa cell proteomes and lipidomes from over two dozen LSD mutants. Global cross-correlation analysis between lipids and proteins identified autophagy defects, notably the accumulation of ferritinophagy substrates and receptors, especially in and mutants, where lysosomes accumulate cholesterol.
View Article and Find Full Text PDFNPC1 controls TGFBR1 stability in a cholesterol transport-independent manner and promotes hepatocellular carcinoma progression.
Nat Commun
January 2025
State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, China.
Niemann-Pick disease type C protein 1 (NPC1), classically associated with cholesterol transport and viral entry, has an emerging role in cancer biology. Here, we demonstrate that knockout of Npc1 in hepatocytes attenuates hepatocellular carcinoma (HCC) progression in both DEN (diethylnitrosamine)-CCl induced and MYC-driven HCC mouse models. Mechanistically, NPC1 significantly promotes HCC progression by modulating the TGF-β pathway, independent of its traditional role in cholesterol transport.
View Article and Find Full Text PDFTwo NPC1 homologous proteins are involved in asexual reproduction, pathogenicity, and lipid trafficking in Phytophthora sojae.
Int J Biol Macromol
January 2025
Department of Plant Pathology, College of Plant Protection, China Agricultural University, Beijing, China; State Key Laboratory of Crop Stress Biology for Arid Areas, College of Plant Protection, Northwest A&F University, Yangling, China. Electronic address:
Niemann-Pick type C (NPC) disease is characterized by lysosomal lipid storage disorders and defects in lipid trafficking, primarily due to mutations in the NPC1 protein. Two NPC1 homologous proteins are present in the genome of Phytophthora sojae, named as PsNPC1-1 and PsNPC1-2. Both proteins exhibit high sequence identity, consistent conserved functional domains, similar gene expression patterns, and comparable subcellular localization.
View Article and Find Full Text PDFL. Methanol Extract and Its Component Rutin Reduce Cholesterol More Efficiently than Miglustat in Niemann-Pick C Fibroblasts.
Int J Mol Sci
October 2024
Department of Biochemistry, University of Veterinary Medicine Hannover, Bünteweg 17, 30559 Hannover, Germany.
Article Synopsis
- - Niemann-Pick type C disease is caused mainly by mutations in the NPC1 gene, leading to cholesterol buildup and lysosomal dysfunction.
- - The study tested polyphenol-rich extracts from *L.* (RCME) and its components, rutin and quercitrin, to see if they could improve NPC1 protein trafficking and reduce cholesterol levels in NPC patient-derived fibroblasts, finding that RCME was effective while the drug miglustat was not.
- - RCME was shown to improve the trafficking of various NPC1 mutants and lower cholesterol levels, suggesting it may be a more effective therapeutic option than current treatments that only reduce cholesterol levels.
Mutant induced neurons and humanized mice enable identification of Niemann-Pick type C1 proteostatic therapies.
JCI Insight
August 2024
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Article Synopsis
- Scientists are looking for medicines that can help fix problems caused by bad versions of proteins in diseases, especially for Niemann-Pick type C1 disease, which affects how cholesterol moves in cells and can cause serious health issues.
- They studied special human brain cells with different types of NPC1 mutations (the bad protein) to find small drugs that could help the protein work better.
- They found a drug called mo56-hydroxycholesterol that helps these mutant proteins and created mice with a common mutation to better understand the disease and test the drug's effects.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!