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 Zietara; Tim Jeske; Maximilian Hastreiter; Meino Rohlfs; Yanshan Liu; Piotr Grabowski; Kaarin Ahomaa; Daniela Maier-Begandt; Marko Schwestka; Vahid Pazhakh; Abdulsalam 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 Zietara, Tim Jeske, Maximilian Hastreiter, Meino Rohlfs, Yanshan Liu, Piotr Grabowski, Kaarin Ahomaa, Daniela Maier-Begandt, Marko Schwestka, Vahid Pazhakh, Abdulsalam 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

School of Biological Sciences

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

Abstract

SRPRA and SRP19 are novel genes affected in congenital neutropenia and essential for granule protein processing.

Comparative proteomics in neutrophil granulocytes

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.

Original language	English
Article number	2022016783
Number of pages	41
Journal	Blood
DOIs	https://doi.org/10.1182/blood.2022016783
Publication status	Published - 11 Oct 2022

Keywords / Materials (for Non-textual outputs)

phagocytes
granulocytes
myelopoiesis

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10.1182/blood.2022016783Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

KleinEtalB2022HumanGeneticDefectsInSRP19AndSRPRAFinal published version, 1.76 MBLicence: Creative Commons: Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND)

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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., ... Klein, C. (2022). Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes. Blood, Article 2022016783. https://doi.org/10.1182/blood.2022016783

@article{b6670f6f36554127adbbe84d2b19f87d,

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

abstract = "SRPRA and SRP19 are novel genes affected in congenital neutropenia and essential for granule protein processing.Comparative proteomics in neutrophil granulocytesThe 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.",

keywords = "phagocytes, granulocytes, myelopoiesis",

author = "Linder, {Monika I.} and Yoko Mizoguchi and Sebastian Hesse and Gergely Csaba and Megumi Tatematsu and Marcin {\L}yszkiewicz and Natalia Zietara 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 Abdulsalam Isiaku 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",

year = "2022",

month = oct,

day = "11",

doi = "10.1182/blood.2022016783",

language = "English",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

}

Linder, MI, 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, 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 2022, 'Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes', Blood. 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 - Zietara, 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

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 - 2022/10/11

Y1 - 2022/10/11

N2 - SRPRA and SRP19 are novel genes affected in congenital neutropenia and essential for granule protein processing.Comparative proteomics in neutrophil granulocytesThe 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.

AB - SRPRA and SRP19 are novel genes affected in congenital neutropenia and essential for granule protein processing.Comparative proteomics in neutrophil granulocytesThe 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.

KW - phagocytes

KW - granulocytes

KW - myelopoiesis

U2 - 10.1182/blood.2022016783

DO - 10.1182/blood.2022016783

M3 - Article

SN - 0006-4971

JO - Blood

JF - Blood

M1 - 2022016783

ER -

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

Abstract

Keywords / Materials (for Non-textual outputs)

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