RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells

Florisela Herrejon Chavez; Hanzhi Luo; Paolo Cifani; Alli Pine; Karen L. Chu; Suhasini Joshi; Ersilia Barin; Alexandra Schurer; Mandy Chan; Kathryn Chang; Grace Y. Q. Han; Aspen J. Pierson; Michael Xiao; Xuejing Yang; Lindsey M. Kuehm; Yuning Hong; Diu T. T. Nguyen; Gabriela Chiosis; Alex Kentsis; Christina Leslie; Ly P. Vu; Michael G. Kharas

RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells

Florisela Herrejon Chavez, Hanzhi Luo, Paolo Cifani, Alli Pine, Karen L. Chu, Suhasini Joshi, Ersilia Barin, Alexandra Schurer, Mandy Chan, Kathryn Chang, Grace Y. Q. Han, Aspen J. Pierson, Michael Xiao, Xuejing Yang, Lindsey M. Kuehm, Yuning Hong, Diu T. T. Nguyen, Gabriela Chiosis, Alex Kentsis, Christina LeslieLy P. Vu, Michael G. Kharas

Memorial Sloan-Kettering Cancer Center

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

10 Scopus citations

Abstract

Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.

Original language	English
Article number	2290
Pages (from-to)	2290
Number of pages	19
Journal	Nature Communications
Volume	14
Issue number	1
State	Published - Apr 21 2023
Externally published	Yes

Keywords

Animals
Gene Expression Regulation
Hematopoietic Stem Cells/metabolism
Heterogeneous-Nuclear Ribonucleoproteins/genetics
Mice
Mice, Knockout
Proteostasis/genetics
RNA-Binding Proteins/genetics

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Herrejon Chavez, F., Luo, H., Cifani, P., Pine, A., Chu, K. L., Joshi, S., Barin, E., Schurer, A., Chan, M., Chang, K., Han, G. Y. Q., Pierson, A. J., Xiao, M., Yang, X., Kuehm, L. M., Hong, Y., Nguyen, D. T. T., Chiosis, G., Kentsis, A., ... Kharas, M. G. (2023). RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells. Nature Communications, 14(1), 2290. Article 2290.

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title = "RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells",

abstract = "Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.",

keywords = "Animals, Gene Expression Regulation, Hematopoietic Stem Cells/metabolism, Heterogeneous-Nuclear Ribonucleoproteins/genetics, Mice, Mice, Knockout, Proteostasis/genetics, RNA-Binding Proteins/genetics",

author = "{Herrejon Chavez}, Florisela and Hanzhi Luo and Paolo Cifani and Alli Pine and Chu, {Karen L.} and Suhasini Joshi and Ersilia Barin and Alexandra Schurer and Mandy Chan and Kathryn Chang and Han, {Grace Y. Q.} and Pierson, {Aspen J.} and Michael Xiao and Xuejing Yang and Kuehm, {Lindsey M.} and Yuning Hong and Nguyen, {Diu T. T.} and Gabriela Chiosis and Alex Kentsis and Christina Leslie and Vu, {Ly P.} and Kharas, {Michael G.}",

note = "{\textcopyright} 2023. The Author(s).",

year = "2023",

month = apr,

day = "21",

language = "English",

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journal = "Nature Communications",

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Herrejon Chavez, F, Luo, H, Cifani, P, Pine, A, Chu, KL, Joshi, S, Barin, E, Schurer, A, Chan, M, Chang, K, Han, GYQ, Pierson, AJ, Xiao, M, Yang, X, Kuehm, LM, Hong, Y, Nguyen, DTT, Chiosis, G, Kentsis, A, Leslie, C, Vu, LP & Kharas, MG 2023, 'RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells', Nature Communications, vol. 14, no. 1, 2290, pp. 2290.

TY - JOUR

T1 - RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells

AU - Herrejon Chavez, Florisela

AU - Luo, Hanzhi

AU - Cifani, Paolo

AU - Pine, Alli

AU - Chu, Karen L.

AU - Joshi, Suhasini

AU - Barin, Ersilia

AU - Schurer, Alexandra

AU - Chan, Mandy

AU - Chang, Kathryn

AU - Han, Grace Y. Q.

AU - Pierson, Aspen J.

AU - Xiao, Michael

AU - Yang, Xuejing

AU - Kuehm, Lindsey M.

AU - Hong, Yuning

AU - Nguyen, Diu T. T.

AU - Chiosis, Gabriela

AU - Kentsis, Alex

AU - Leslie, Christina

AU - Vu, Ly P.

AU - Kharas, Michael G.

PY - 2023/4/21

Y1 - 2023/4/21

N2 - Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.

AB - Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.

KW - Animals

KW - Gene Expression Regulation

KW - Hematopoietic Stem Cells/metabolism

KW - Heterogeneous-Nuclear Ribonucleoproteins/genetics

KW - Mice

KW - Mice, Knockout

KW - Proteostasis/genetics

KW - RNA-Binding Proteins/genetics

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M3 - Article

C2 - 37085479

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VL - 14

SP - 2290

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2290

ER -

RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells

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Keywords

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