Regulation of perforin activation and pre‐synaptic toxicity through C‐terminal glycosylation
| Autor: | Omer Gilan, Colin M. House, Joseph A. Trapani, Ilia Voskoboinik, Ruby H. P. Law, Imran G House, James C. Whisstock, Mark A. Dawson, Amelia Jean Brennan |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Glycosylation Immunological Synapses chemical and pharmacologic phenomena Biology Cytoplasmic Granules Endoplasmic Reticulum Biochemistry Natural killer cell Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Animals Humans Cytotoxic T cell Secretion Molecular Biology MACPF Membrane Glycoproteins Perforin Endoplasmic reticulum Scientific Reports Degranulation Cell biology Killer Cells Natural Granzyme B 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Proteolysis biology.protein Interleukin-2 Protein Processing Post-Translational |
| Zdroj: | EMBO reports. 18:1775-1785 |
| ISSN: | 1469-3178 1469-221X |
| Popis: | Perforin is a highly cytotoxic pore‐forming protein essential for immune surveillance by cytotoxic lymphocytes. Prior to delivery to target cells by exocytosis, perforin is stored in acidic secretory granules where it remains functionally inert. However, how cytotoxic lymphocytes remain protected from their own perforin prior to its export to secretory granules, particularly in the Ca2+‐rich endoplasmic reticulum, remains unknown. Here, we show that N‐linked glycosylation of the perforin C‐terminus at Asn549 within the endoplasmic reticulum inhibits oligomerisation of perforin monomers and thus protects the host cell from premature pore formation. Subsequent removal of this glycan occurs through proteolytic processing of the C‐terminus within secretory granules and is imperative for perforin activation prior to secretion. Despite evolutionary conservation of the C‐terminus, we found that processing is carried out by multiple proteases, which we attribute to the unstructured and exposed nature of the region. In sum, our studies reveal a post‐translational regulatory mechanism essential for maintaining perforin in an inactive state until its secretion from the inhibitory acidic environment of the secretory granule. |
| Databáze: | OpenAIRE |
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