RNA-binding protein HuR suppresses senescence through Atg7 mediated autophagy activation in diabetic intervertebral disc degeneration

  • Cell Prolif. 2021 Feb;54(2):e12975. doi: 10.1111/cpr.12975.
Zhenxuan Shao  1  2  3 ,  Libin Ni  1  2  3 ,  Sunli Hu  1  2  3 ,  Tianzhen Xu  1  4 ,  Zaher Meftah  1  2  3 ,  Zupo Yu  1  2  3 ,  Naifeng Tian  1  2  3 ,  Yaosen Wu  1  2  3 ,  Liaojun Sun  1  2  3 ,  Aimin Wu  1  2  3 ,  Zongyou Pan  5 ,  Linwei Chen  5 ,  Weiyang Gao  1  2  3 ,  Yifei Zhou  1  2  3 ,  Xiaolei Zhang  1  2  3 ,  Xiangyang Wang  1  2  3
Affiliations
  • 1. Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
  • 2. Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China.
  • 3. The Second School of Medicine, Wenzhou Medical University, Wenzhou, China.
  • 4. Department of Orthopaedics, Zhuji People's Hospital of Zhejiang Province, China.
  • 5. Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
PMID: 33372336 DOI: 10.1111/cpr.12975
Abstract

Objectives: Diabetes is a risk factor for intervertebral disc degeneration (IVDD). Studies have demonstrated that diabetes may affect IVDD through transcriptional regulation; however, whether post-transcriptional regulation is involved in diabetic IVDD (DB-IVDD) is still unknown. This study was performed to illustrate the role of HuR, an RNA-binding protein, in DB-IVDD development and its mechanism.

Materials and methods: The expression of HuR was evaluated in nucleus pulposus (NP) tissues from diabetic IVDD patients and in high glucose-treated NP cells. Senescence and Autophagy were assessed in HuR over-expressing and downregulation NP cells. The mRNAs that were regulated by HuR were screened, and immunoprecipitation was applied to confirm the regulation of HuR on targeted mRNAs.

Results: The results showed that the expression of HuR was decreased in diabetic NP tissues and high glucose-treated NP cells. Downregulation of HuR may lead to increased senescence in high glucose-treated NP cells, while Autophagy activation attenuates senescence in HuR deficient NP cells. Mechanistic study showed that HuR prompted Atg7 mRNA stability via binding to the AU-rich elements. Furthermore, overexpression of Atg7, but not HuR, may ameliorate DB-IVDD in rats in vivo.

Conclusions: In conclusion, HuR may suppress senescence through Autophagy activation via stabilizing Atg7 in diabetic NP cells; while Atg7, but not HuR, may serve as a potential therapeutic target for DB-IVDD.

Keywords
Atg7; HuR; autophagy; diabetes; intervertebral disc degeneration; senescence.
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