Golgi-58K can re-localize to late endosomes upon cellular uptake of PS-ASOs and facilitates endosomal release of ASOs
| Autor: | Hong Sun, Joshua G Nichols, Stanley T. Crooke, Lingdi Zhang, Cheryl L De Hoyos, Xue-hai Liang |
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| Rok vydání: | 2021 |
| Předmět: |
AcademicSubjects/SCI00010
Endosome RNase P Ribonuclease H Golgi Apparatus Phosphorothioate Oligonucleotides Endosomes Biology Cleavage (embryo) Receptor IGF Type 2 03 medical and health sciences symbols.namesake Organelle Gene expression Genetics Humans Molecular Biology Late endosome 030304 developmental biology 0303 health sciences Membrane Glycoproteins 030302 biochemistry & molecular biology Golgi Matrix Proteins Biological Transport Oligonucleotides Antisense Golgi apparatus Endocytosis Cell biology symbols Axoplasmic transport HeLa Cells |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| DOI: | 10.1093/nar/gkab599 |
| Popis: | Phosphorothioate (PS) modified antisense oligonucleotide (ASO) drugs can trigger RNase H1 cleavage of cellular target RNAs to modulate gene expression. Internalized PS-ASOs must be released from membraned endosomal organelles, a rate limiting step that is not well understood. Recently we found that M6PR transport between Golgi and late endosomes facilitates productive release of PS-ASOs, raising the possibility that Golgi-mediated transport may play important roles in PS-ASO activity. Here we further evaluated the involvement of Golgi in PS-ASO activity by examining additional Golgi proteins. Reduction of certain Golgi proteins, including Golgi-58K, GCC1 and TGN46, decreased PS-ASO activity, without substantial effects on Golgi integrity. Upon PS-ASO cellular uptake, Golgi-58K was recruited to late endosomes where it colocalized with PS-ASOs. Reduction of Golgi-58K caused slower PS-ASO release from late endosomes, decreased GCC2 late endosome relocalization, and led to slower retrograde transport of M6PR from late endosomes to trans-Golgi. Late endosome relocalization of Golgi-58K requires Hsc70, and is most likely mediated by PS-ASO–protein interactions. Together, these results suggest a novel function of Golgi-58K in mediating Golgi-endosome transport and indicate that the Golgi apparatus plays an important role in endosomal release of PS-ASO, ensuring antisense activity. |
| Databáze: | OpenAIRE |
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