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

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 revea...

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Bibliographic Details
Published in:	Nature communications Vol. 14; no. 1; pp. 2290 - 19
Main Authors:	Herrejon Chavez, Florisela, Luo, Hanzhi, Cifani, Paolo, Pine, Alli, Chu, Eren L., Joshi, Suhasini, Barin, Ersilia, Schurer, Alexandra, Chan, Mandy, Chang, Kathryn, Han, Grace Y. Q., Pierson, Aspen J., Xiao, Michael, Yang, Xuejing, Kuehm, Lindsey M., Hong, Yuning, Nguyen, Diu T. T., Chiosis, Gabriela, Kentsis, Alex, Leslie, Christina, Vu, Ly P., Kharas, Michael G.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 21-04-2023 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/100 13/106 49/31 631/136/232 631/45/500 631/532/1542 Animals Blood Cdc42 protein Cell self-renewal Defects Dilution Endoplasmic reticulum Gene Expression Regulation Guanine nucleotide-binding protein Hematopoietic stem cells Hematopoietic Stem Cells - metabolism Heterogeneous-Nuclear Ribonucleoproteins - genetics Heterogeneous-Nuclear Ribonucleoproteins - metabolism Homeostasis Humanities and Social Sciences Maintenance Mice Mice, Knockout multidisciplinary Polarity Post-transcription Progenitor cells Protein biosynthesis Protein folding Protein synthesis Proteins Proteomes Proteostasis - genetics Repopulation RNA-binding protein RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Science Science (multidisciplinary) Stem cells Transplantation
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Summary:	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. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here they show that SYNCRIP safeguards HSC self-renewal during regenerative stress by maintaining both proteostasis and CDC42-regulated cell polarity.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-38001-x