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ResearchIn-Press PreviewBone biology Open Access | 10.1172/JCI165140

Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis-dependent intervertebral disc inflammatory degeneration

Weifeng Zhang,1 Gaocai Li,1 Xingyu Zhou,1 Huaizhen Liang,1 Bide Tong,1 Di Wu,1 Kevin Yang,2 Yu Song,1 Bingjin Wang,1 Zhiwei Liao,1 Liang Ma,1 Wencan Ke,1 Xiaoguang Zhang,1 Jie Lei,1 Chunchi Lei,1 Xiaobo Feng,1 Kun Wang,1 Kangcheng Zhao,1 and Cao Yang1

1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

Find articles by Zhao, K. in: PubMed | Google Scholar

1Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

2Wuhan Britain-China School, Wuhan Britain-China School, Wuhan, China

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Published January 23, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI165140.
Copyright © 2024, Zhang et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 23, 2024 - Version history
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Abstract

Given the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socio-economic challenge to the aging population, which is importantly attributed to intervertebral disc degeneration (IVDD). Elastic nucleus pulposus (NP) tissue is essential for the maintenance of IVD structural and functional integrity. The accumulation of senescent NP cells with inflammatory hypersecretory phenotype due to aging and other damaged factors is a distinctive hallmark of IVDD initiation and progression. In this study, we revealed a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cGAS-STING axis but not AIM2 inflammasome assembly. ATR deficiency destroyed genomic integrity and led to cytosolic mislocalization of genomic DNA, which acted as a powerful driver of cGAS-STING axis-dependent inflammatory phenotype acquisition during NP cell senescence. Mechanically, the disassembly of ATR-TRIM56 complex with the enzyme activity liberation of USP5 and TRIM25 drove change in ATR ubiquitination, with ATR switching from K63-linked modification to K48-linked modification, promoting ubiquitin-proteasome-dependent dynamic instability of ATR protein during NP cell senescent progression. Importantly, an engineered extracellular vesicle (EV)-based strategy for delivering ATR-overexpressing plasmid cargo efficiently diminished DNA damage-associated NP cell senescence and substantially mitigated IVDD progression, indicating promising targets and efficient approaches for ameliorating the impact of IVDD.

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Version history
  • Version 1 (January 23, 2024): In-Press Preview
  • Version 2 (March 15, 2024): Electronic publication
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