Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
09 02 2023
09 02 2023
Historique:
accepted:
15
08
2022
received:
22
04
2022
pubmed:
13
10
2022
medline:
14
2
2023
entrez:
12
10
2022
Statut:
ppublish
Résumé
The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover 2 novel human genetic defects in signal recognition particle receptor alpha (SRPRA) and SRP19, constituents of the mammalian cotranslational targeting machinery, and characterize their roles in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the 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.
Identifiants
pubmed: 36223592
pii: S0006-4971(22)07729-1
doi: 10.1182/blood.2022016783
pmc: PMC10651786
doi:
Substances chimiques
signal peptide receptor
0
Proteome
0
HAX1 protein, human
0
Adaptor Proteins, Signal Transducing
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
645-658Informations de copyright
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
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