Age-related noncanonical TRMT6-TRMT61A signaling impairs hematopoietic stem cells

Hanqing He; Yuqian Wang; Xiaoting Zhang; Xiaoyu Li; Chao Liu; Dingfei Yan; Haiteng Deng; Wanling Sun; Chengqi Yi; Jianwei Wang

doi:10.1038/s43587-023-00556-1

Age-related noncanonical TRMT6-TRMT61A signaling impairs hematopoietic stem cells

Nat Aging. 2024 Feb;4(2):213-230. doi: 10.1038/s43587-023-00556-1. Epub 2024 Jan 17.

Authors

Hanqing He^#¹, Yuqian Wang^#¹, Xiaoting Zhang^#², Xiaoyu Li^#², Chao Liu³, Dingfei Yan⁴, Haiteng Deng⁴, Wanling Sun⁵, Chengqi Yi^{6

7}, Jianwei Wang^{8

9}

Affiliations

¹ School of Pharmaceutical Sciences, Tsinghua University, Beijing, China.
² State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
³ Department of Laboratory Animal Science, Hebei Key Lab of Hebei Laboratory Animal Science, Hebei Medical University, Shijiazhuang, P. R. China.
⁴ MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
⁵ Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, China.
⁶ State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China. chengqi.yi@pku.edu.cn.
⁷ Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China. chengqi.yi@pku.edu.cn.
⁸ School of Pharmaceutical Sciences, Tsinghua University, Beijing, China. jianweiwang@mail.tsinghua.edu.cn.
⁹ State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China. jianweiwang@mail.tsinghua.edu.cn.

^# Contributed equally.

PMID: 38233630
DOI: 10.1038/s43587-023-00556-1

Abstract

Aged hematopoietic stem cells (HSCs) exhibit compromised reconstitution capacity and differentiation bias toward myeloid lineages. However, the molecular mechanism behind HSC aging remains largely unknown. In this study, we observed that RNA N¹-methyladenosine-generating methyltransferase TRMT6-TRMT61A complex is increased in aged murine HSCs due to aging-declined CRL4^DCAF1-mediated ubiquitination degradation signaling. Unexpectedly, no difference of tRNA N¹-methyladenosine methylome is observed between young and aged hematopoietic stem and progenitor cells, suggesting a noncanonical role of the TRMT6-TRMT61A complex in the HSC aging process. Further investigation revealed that enforced TRMT6-TRMT61A impairs HSCs through 3'-tiRNA-Leu-CAG and subsequent RIPK1-RIPK3-MLKL-mediated necroptosis cascade. Deficiency of necroptosis ameliorates the self-renewal capacity of HSCs and counters the physiologically deleterious effect of enforced TRMT6-TRMT61A on HSCs. Together, our work uncovers a nonclassical role for the TRMT6-TRMT61A complex in HSC aging and highlights a therapeutic target.

MeSH terms

Aging / genetics
Animals
Cell Differentiation / genetics
Hematopoietic Stem Cells*
Mice
Signal Transduction*

Abstract

MeSH terms

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