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Linder, M.I.* ; Mizoguchi, Y.* ; Hesse, S.* ; Csaba, G.* ; Tatematsu, M.* ; Łyszkiewicz, M.* ; Ziętara, 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.*

Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes.

Blood 141, 645-658 (2023)
Verlagsversion Postprint DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Signal Recognition Particle; Matrix Protein; Mutations; Neutrophils; Granules; Translocation; Induce
ISSN (print) / ISBN 0006-4971
e-ISSN 1528-0020
Zeitschrift Blood
Quellenangaben Band: 141, Heft: 6, Seiten: 645-658 Artikelnummer: , Supplement: ,
Verlag American Society of Hematology
Verlagsort 2021 L St Nw, Suite 900, Washington, Dc 20036 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Bioinformatics and Systems Biology (IBIS)
Institute of Stem Cell Research (ISF)
Förderungen
Junior Researcher Fund of Ludwig-Maximilians-Universitaet Excellence Initiative
Monash University
Maddie Riewoldt's Vision
National Health and Medical Research Council
Australian Government
State Government of Victoria
Wilson Centre for Lymphoma Genomics through the Snowdome Foundation
Care-for-Rare Foundation
BMBF (PIDNET)
DFG, Gottfried Wilhelm Leibniz Program