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

Herrejon Chavez, Florisela, Luo, Hanzhi, Cifani, Paolo, Pine, Alli, Chu, Karen L, Joshi, Suhasini, Barin, Ersilia, Schurer, Alexandra, Chan, Mandy, Chang, Kathryn, Han, Grace YQ, Pierson, Aspen J, Xiao, Michael, Yang, Xuejing, Kuehm, Lindsey M, Hong, Yuning, Nguyen, Diu TT, Chiosis, Gabriela, Kentsis, Alex, Leslie, Christina, Vu, Ly P, Kharas, Michael G (April 2023) RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells. Nature Communications, 14 (1). p. 2290. ISSN 2041-1723 (Public Dataset)

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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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types > hematopoietic cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > hematopoietic cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > hematopoietic cell organism description > animal > mammal organism description > animal > mammal > rodent > mouse bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > nuclear ribonucleoprotein bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > RNA binding protein organism description > animal > mammal > rodent
CSHL Authors:	Cifani, Paolo
Communities:	CSHL labs > Cifani lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	21 April 2023
Date Deposited:	21 Jun 2023 13:09
Last Modified:	10 Jan 2024 19:16
PMCID:	PMC10121618
Related URLs:	Publisher
Dataset ID:	GEO: GSE202421 GEO: GSE202463 GEO: GSE202464 ProteomeXchange Consortium: PXD019779
URI:	https://repository.cshl.edu/id/eprint/40891

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