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

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

doi:10.1182/blood.2022016783

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

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. SaitoEjona 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

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 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.

Original language	English
Pages (from-to)	645-658
Number of pages	14
Journal	Blood
Volume	141
Issue number	6
DOIs	https://doi.org/10.1182/blood.2022016783
State	Published - 9 Feb 2023
Externally published	Yes

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Linder, M. I., Mizoguchi, Y., Hesse, S., Csaba, G., Tatematsu, M., Łyszkiewicz, M., Ziȩtara, N., Jeske, T., Hastreiter, M., Rohlfs, M., Liu, Y., Grabowski, P., Ahomaa, K., Maier-Begandt, D., Schwestka, M., Pazhakh, V., Isiaku, A. I., Briones Miranda, B., Blombery, P., ... Klein, C. (2023). Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes. Blood, 141(6), 645-658. https://doi.org/10.1182/blood.2022016783

@article{5fd0b179ba464ecd96e185bcbfa52d12,

title = "Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes",

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 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.",

author = "Linder, \{Monika I.\} and Yoko Mizoguchi and Sebastian Hesse and Gergely Csaba and Megumi Tatematsu and Marcin {\L}yszkiewicz and Natalia Ziȩtara and Tim Jeske and Maximilian Hastreiter and Meino Rohlfs and Yanshan Liu and Piotr Grabowski and Kaarin Ahomaa and Daniela Maier-Begandt and Marko Schwestka and Vahid Pazhakh and Isiaku, \{Abdulsalam I.\} and \{Briones Miranda\}, Brenda and Piers Blombery and Saito, \{Megumu K.\} and Ejona Rusha and Zahra Alizadeh and Zahra Pourpak and Masao Kobayashi and Nima Rezaei and Ekrem Unal and Fabian Hauck and Micha Drukker and Barbara Walzog and Juri Rappsilber and Ralf Zimmer and Lieschke, \{Graham J.\} and Christoph Klein",

note = "Publisher Copyright: {\textcopyright} 2023 The American Society of Hematology",

year = "2023",

month = feb,

day = "9",

doi = "10.1182/blood.2022016783",

language = "English",

volume = "141",

pages = "645--658",

journal = "Blood",

issn = "0006-4971",

number = "6",

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Linder, MI, Mizoguchi, Y, Hesse, S, Csaba, G, Tatematsu, M, Łyszkiewicz, M, Ziȩtara, N, Jeske, T, Hastreiter, M, Rohlfs, M, Liu, Y, Grabowski, P, Ahomaa, K, Maier-Begandt, D, Schwestka, M, Pazhakh, V, Isiaku, AI, Briones Miranda, B, Blombery, P, Saito, MK, Rusha, E, Alizadeh, Z, Pourpak, Z, Kobayashi, M, Rezaei, N, Unal, E, Hauck, F, Drukker, M, Walzog, B, Rappsilber, J, Zimmer, R, Lieschke, GJ & Klein, C 2023, 'Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes', Blood, vol. 141, no. 6, pp. 645-658. https://doi.org/10.1182/blood.2022016783

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

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 -

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

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