Long noncoding RNA MAGI2-AS3 regulates the H2O2 level and cell senescence via HSPA8

Yingmin Zhang; Xinhua Qiao; Lihui Liu; Wensheng Han; Qinghua Liu; Yuanyuan Wang; Ting Xie; Yiheng Tang; Tiepeng Wang; Jiao Meng; Aojun Ye; Shunmin He; Runsheng Chen; Chang Chen

doi:10.1016/j.redox.2022.102383

Long noncoding RNA MAGI2-AS3 regulates the H₂O₂ level and cell senescence via HSPA8

Redox Biol. 2022 Aug:54:102383. doi: 10.1016/j.redox.2022.102383. Epub 2022 Jun 30.

Authors

Yingmin Zhang¹, Xinhua Qiao², Lihui Liu³, Wensheng Han¹, Qinghua Liu³, Yuanyuan Wang¹, Ting Xie¹, Yiheng Tang⁴, Tiepeng Wang², Jiao Meng², Aojun Ye¹, Shunmin He⁴, Runsheng Chen⁴, Chang Chen⁵

Affiliations

¹ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
² National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
³ Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
⁴ University of Chinese Academy of Sciences, Beijing, 100049, China; Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
⁵ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: changchen@ibp.ac.cn.

Abstract

The redox homeostasis system regulates many biological processes, intracellular antioxidant production and redox signaling. However, long noncoding RNAs (lncRNAs) involved in redox regulation have rarely been reported. Herein, we reported that downregulation of MAGI2-AS3 decreased the superoxide level in Human fibroblasts (Fbs), a replicative aging model, as detected by the fluorescent probes dihydroethidium (DHE) and MitoSOX™ Red. RNA pulldown combined with mass spectrometry showed that HSPA8 is a novel interacting protein of MAGI2-AS3, which was further confirmed by photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP). Downregulation of MAGI2-AS3 decreased the hydrogen peroxide (H₂O₂) content by stabilizing the HSPA8 protein level via inhibiting the protesome degradation of HSPA8. Further evidence showed that MAGI2-AS3 interacted with the C-terminal domain (CTD) of HSPA8. Downregulation of MAGI2-AS3 delayed cell senescence, while this antiaging effect was abolished by HSPA8 knockdown. The underlying molecular mechanism by which MAGI2-AS3 knockdown inhibited cell senescence was mediated via suppression of the ROS/MAP2K6/p38 signaling pathway. Taken together, these findings revealed that downregulation of lncRNA MAGI2-AS3 decreased the H₂O₂ content and delayed cell senescence by stabilizing the HSPA8 protein level, identifying a potential antiaging application.

Keywords: Cell senescence; HSPA8; Long noncoding RNA; MAGI2-AS3.

MeSH terms

Cell Line, Tumor
Cell Proliferation / genetics
Cellular Senescence
Gene Expression Regulation, Neoplastic
HSC70 Heat-Shock Proteins* / metabolism
Humans
Hydrogen Peroxide / metabolism
MicroRNAs* / genetics
RNA, Long Noncoding* / genetics

Substances

HSC70 Heat-Shock Proteins
HSPA8 protein, human
MicroRNAs
RNA, Long Noncoding
Hydrogen Peroxide