PUBLICATION
Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes
- Authors
- 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.
- ID
- ZDB-PUB-221018-35
- Date
- 2022
- Source
- Blood 141(6): 645-658 (Journal)
- Registered Authors
- BRIONES MIRANDA, Brenda, Lieschke, Graham J., Maier-Begandt, Daniela, Pazhakh, Vahid
- Keywords
- none
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing
- Animals
- Human Genetics
- Humans
- Induced Pluripotent Stem Cells*
- Mammals
- Proteome*
- Zebrafish
- PubMed
- 36223592 Full text @ Blood
Citation
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. 141(6):645-658.
Abstract
The 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping