TY - JOUR
T1 - Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes
AU - Linder, Monika I.
AU - Mizoguchi, Yoko
AU - Hesse, Sebastian
AU - Csaba, Gergely
AU - Tatematsu, Megumi
AU - Łyszkiewicz, Marcin
AU - Ziȩtara, Natalia
AU - Jeske, Tim
AU - Hastreiter, Maximilian
AU - Rohlfs, Meino
AU - Liu, Yanshan
AU - Grabowski, Piotr
AU - Ahomaa, Kaarin
AU - Maier-Begandt, Daniela
AU - Schwestka, Marko
AU - Pazhakh, Vahid
AU - Isiaku, Abdulsalam I.
AU - Briones Miranda, Brenda
AU - Blombery, Piers
AU - Saito, Megumu K.
AU - Rusha, Ejona
AU - Alizadeh, Zahra
AU - Pourpak, Zahra
AU - Kobayashi, Masao
AU - Rezaei, Nima
AU - Unal, Ekrem
AU - Hauck, Fabian
AU - Drukker, Micha
AU - Walzog, Barbara
AU - Rappsilber, Juri
AU - Zimmer, Ralf
AU - Lieschke, Graham J.
AU - Klein, Christoph
N1 - Publisher Copyright:
© 2023 The American Society of Hematology
PY - 2023/2/9
Y1 - 2023/2/9
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85145182715
U2 - 10.1182/blood.2022016783
DO - 10.1182/blood.2022016783
M3 - Article
C2 - 36223592
AN - SCOPUS:85145182715
SN - 0006-4971
VL - 141
SP - 645
EP - 658
JO - Blood
JF - Blood
IS - 6
ER -