On the shuttling across the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias
| Autor: | Aroa Duro-Castano, Lena Harker-Kirschneck, Anđela Šarić, Xiaohe Tian, Lei Luo, Joe Forth, Edoardo Scarpa, Pan Xiang, Sophie Nyberg, Zhongping Zhang, Manish R. Vuyyuru, Gavin Fullstone, Yupeng Tian, Azzurra Apriceno, Diana Matias, Loris Rizzello, Diana Moreira Leite, Bin Fang, Alessandro Poma, Giuseppe Battaglia |
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| Rok vydání: | 2020 |
| Předmět: |
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Endocytic cycle education Central nervous system macromolecular substances Endocytosis Blood–brain barrier environment and public health Clathrin 03 medical and health sciences 0302 clinical medicine parasitic diseases medicine Avidity Internalization Research Articles health care economics and organizations Dynamin 030304 developmental biology media_common 0303 health sciences Multidisciplinary biology Chemistry SciAdv r-articles Cell Biology LRP1 In vitro 3. Good health medicine.anatomical_structure Transcytosis Amphiphysin biology.protein Biophysics 030217 neurology & neurosurgery Intracellular Research Article |
| Zdroj: | Science Advances bioRxiv |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.abc4397 |
| Popis: | Tubule formation acts as cargo transport across the blood-brain barrier. The blood-brain barrier is made of polarized brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Although transport across BECs is of paramount importance for nutrient uptake as well as ridding the brain of waste products, the intracellular sorting mechanisms that regulate successful receptor-mediated transcytosis in BECs remain to be elucidated. Here, we used a synthetic multivalent system with tunable avidity to the low-density lipoprotein receptor–related protein 1 (LRP1) to investigate the mechanisms of transport across BECs. We used a combination of conventional and super-resolution microscopy, both in vivo and in vitro, accompanied with biophysical modeling of transport kinetics and membrane-bound interactions to elucidate the role of membrane-sculpting protein syndapin-2 on fast transport via tubule formation. We show that high-avidity cargo biases the LRP1 toward internalization associated with fast degradation, while mid-avidity augments the formation of syndapin-2 tubular carriers promoting a fast shuttling across. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
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