Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes
| Autor: | Monika I. Linder, Yoko Mizoguchi, Sebastian Hesse, Gergely Csaba, Megumi Tatematsu, Marcin Łyszkiewicz, Natalia Ziȩtara, Tim Jeske, Maximilian Hastreiter, Meino Rohlfs, Yanshan Liu, Piotr Grabowski, Kaarin Ahomaa, Daniela Maier-Begandt, Marko Schwestka, Vahid Pazhakh, Abdulsalam I. Isiaku, Brenda Briones Miranda, Piers Blombery, Megumu K. Saito, Ejona Rusha, Zahra Alizadeh, Zahra Pourpak, Masao Kobayashi, Nima Rezaei, Ekrem Unal, Fabian Hauck, Micha Drukker, Barbara Walzog, Juri Rappsilber, Ralf Zimmer, Graham J. Lieschke, Christoph Klein |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Linder, M I, Mizoguchi, Y, Hesse, S, Csaba, G, Tatematsu, M, Łyszkiewicz, M, Zietara, N, Jeske, T, Hastreiter, M, Rohlfs, M, Liu, Y, Grabowski, P, Ahomaa, K, Maier-Begandt, D, Schwestka, M, Pazhakh, V, Isiaku, A, Briones Miranda, B, Blombery, P, Saito, M K, Rusha, E, Alizadeh, Z, Pourpak, Z, Kobayashi, M, Rezaei, N, Unal, E, Hauck, F, Drukker, M, Walzog, B, Rappsilber, J, Zimmer, R, Lieschke, G J & Klein, C 2022, ' Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes ', Blood . https://doi.org/10.1182/blood.2022016783 Blood 141, 645-658 (2023) |
| DOI: | 10.1182/blood.2022016783 |
| Popis: | SRPRA and SRP19 are novel genes affected in congenital neutropenia and essential for granule protein processing.Comparative proteomics in neutrophil granulocytesThe mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover two novel human genetic defects in SRPRA and SRP19, constituents of the mammalian co-translational targeting machinery and characterize their role in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the signal recognition particle (SRP) genes, HAX1, and ELANE and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP-deficiency on neutrophil granulocyte development. In a heterologous cell-based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking and homeostasis are critically important for the differentiation of neutrophil granulocytes. |
| Databáze: | OpenAIRE |
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