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RNA 结合蛋白 HuR 通过 Atg7 介导的自噬激活抑制糖尿病性椎间盘退变中的衰老。

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

机构信息

Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, China.

出版信息

Cell Prolif. 2021 Feb;54(2):e12975. doi: 10.1111/cpr.12975. Epub 2020 Dec 28.

DOI:10.1111/cpr.12975
PMID:33372336
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7848958/
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.

摘要

目的

糖尿病是椎间盘退行性变（IVDD）的一个危险因素。研究表明，糖尿病可能通过转录调控影响 IVDD；然而，糖尿病性 IVDD（DB-IVDD）是否涉及转录后调控尚不清楚。本研究旨在阐明 RNA 结合蛋白 HuR 在 DB-IVDD 发病机制中的作用及其机制。

材料和方法

评估糖尿病 IVDD 患者的髓核组织和高糖处理的髓核细胞中 HuR 的表达。在 HuR 过表达和下调的髓核细胞中评估衰老和自噬。筛选受 HuR 调控的 mRNAs，并应用免疫沉淀法证实 HuR 对靶向 mRNAs 的调控。

结果

结果表明，HuR 在糖尿病性 NP 组织和高糖处理的 NP 细胞中的表达降低。HuR 的下调可能导致高糖处理的 NP 细胞中衰老增加，而自噬激活减轻 HuR 缺陷 NP 细胞中的衰老。机制研究表明，HuR 通过与富含 AU 的元件结合来促进 Atg7 mRNA 的稳定性。此外，Atg7 的过表达，而不是 HuR，可能在体内改善大鼠的 DB-IVDD。

结论

总之，HuR 可能通过稳定糖尿病性 NP 细胞中的 Atg7 来通过自噬激活抑制衰老；而 Atg7 而不是 HuR 可能是 DB-IVDD 的潜在治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/350295c6b19d/CPR-54-e12975-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/3cb8b042e9ed/CPR-54-e12975-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/2c850e47b0ab/CPR-54-e12975-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/7b9a47ff3290/CPR-54-e12975-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/b41e886069f1/CPR-54-e12975-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/350295c6b19d/CPR-54-e12975-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/3cb8b042e9ed/CPR-54-e12975-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/76ccc6edfcd3/CPR-54-e12975-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/1647ca31248b/CPR-54-e12975-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/2c850e47b0ab/CPR-54-e12975-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/7b9a47ff3290/CPR-54-e12975-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/b41e886069f1/CPR-54-e12975-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9d33/7848958/350295c6b19d/CPR-54-e12975-g008.jpg

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