Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing

Xuan Gu; Kailing Li; Meng Zhang; Yandan Chen; Jingchao Zhou; Chunxu Yao; Yong Zang; Jiefeng He; Jun Wan; Bin Guo

doi:10.1016/j.celrep.2023.113264

Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing

Cell Rep. 2023 Oct 31;42(10):113264. doi: 10.1016/j.celrep.2023.113264. Epub 2023 Oct 14.

Authors

Xuan Gu¹, Kailing Li², Meng Zhang¹, Yandan Chen¹, Jingchao Zhou¹, Chunxu Yao¹, Yong Zang³, Jiefeng He⁴, Jun Wan⁵, Bin Guo⁶

Affiliations

¹ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Department of BioHealth Informatics, Indiana University School of Informatics and Computing at IUPUI, Indianapolis, IN 46202, USA.
³ Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁴ Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan 030032, China. Electronic address: jfhe@sxmu.edu.cn.
⁵ Department of BioHealth Informatics, Indiana University School of Informatics and Computing at IUPUI, Indianapolis, IN 46202, USA; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: junwan@iu.edu.
⁶ Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Department of Hematology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China. Electronic address: jybinguo@shsmu.edu.cn.

PMID: 37838946
DOI: 10.1016/j.celrep.2023.113264

Abstract

Aspartyl-tRNA synthetase 2 (Dars2) is involved in the regulation of mitochondrial protein synthesis and tissue-specific mitochondrial unfolded protein response (UPR^mt). The role of Dars2 in the self-renewal and differentiation of hematopoietic stem cells (HSCs) is unknown. Here, we show that knockout (KO) of Dars2 significantly impairs the maintenance of hematopoietic stem and progenitor cells (HSPCs) without involving its tRNA synthetase activity. Dars2 KO results in significantly reduced expression of Srsf2/3/6 and impairs multiple events of mRNA alternative splicing (AS). Dars2 directly localizes to Srsf3-labeled spliceosomes in HSPCs and regulates the stability of Srsf3. Dars2-deficient HSPCs exhibit aberrant AS of mTOR and Slc22a17. Dars2 KO greatly suppresses the levels of labile ferrous iron and iron-sulfur cluster-containing proteins, which dampens mitochondrial metabolic activity and DNA damage repair pathways in HSPCs. Our study reveals that Dars2 plays a crucial role in the iron-sulfur metabolism and maintenance of HSPCs by modulating RNA splicing.

Keywords: CP: Metabolism; CP: Stem cell research.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing* / genetics
Aspartate-tRNA Ligase* / genetics
Aspartate-tRNA Ligase* / metabolism
Hematopoietic Stem Cells / metabolism
Iron / metabolism
Mitochondria / metabolism

Substances

Aspartate-tRNA Ligase
Iron