Disassembly of the TRIM56-ATR complex promotes cytoDNA/cGAS/STING axis–dependent intervertebral disc inflammatory degeneration
Weifeng Zhang, … , Kangcheng Zhao, Cao Yang
Weifeng Zhang, … , Kangcheng Zhao, Cao Yang
Published January 23, 2024
Citation Information: J Clin Invest. 2024;134(6):e165140. https://doi.org/10.1172/JCI165140.
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Research Article Bone biology

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

Abstract

As the leading cause of disability worldwide, low back pain (LBP) is recognized as a pivotal socioeconomic challenge to the aging population and is largely 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 an inflammatory hypersecretory phenotype due to aging and other damaging factors is a distinctive hallmark of IVDD initiation and progression. In this study, we reveal a mechanism of IVDD progression in which aberrant genomic DNA damage promoted NP cell inflammatory senescence via activation of the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) axis but not of absent in melanoma 2 (AIM2) inflammasome assembly. Ataxia-telangiectasia–mutated and Rad3-related protein (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. Mechanistically, disassembly of the ATR–tripartite motif–containing 56 (ATR-TRIM56) complex with the enzymatic liberation of ubiquitin-specific peptidase 5 (USP5) and TRIM25 drove changes in ATR ubiquitination, with ATR switching from K63- to K48-linked modification, c thereby promoting ubiquitin-proteasome–dependent dynamic instability of ATR protein during NP cell senescence progression. Importantly, an engineered extracellular vesicle–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 effective approaches to ameliorate the chronic pain and disabling effects of IVDD.

Authors

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

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Figure 15

EV-based ATR-overexpressing plasmid cargo exhibits efficient therapeutic effects in ameliorating the severity of IVDD.

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EV-based ATR-overexpressing plasmid cargo exhibits efficient therapeutic...
(A–C) Representative in vivo images of coccygeal IVDs in rats immediately after treatment with the intradisc injection of ATR-EVs or vector-EVs and representative MRIs of rat coccygeal IVDs treated with an intradisc injection of ATR-EVs or vector-EVs for 4 weeks (n = 5). (D–F) H&E staining and SO&FG staining of rat coccygeal IVDs. Scale bar: 1 mm. (G–I) IF staining of DiI-labeled EVs in rat coccygeal IVDs (scale bars: 50 μm) and IHC staining of ATR, p-p53, and γH2A expression in rat coccygeal IVDs (scale bars: 250 μm). (J–L) Disc height index (J) (n = 15 biological replicates), Pfirrmann degenerative grades (K) (n = 15 biological replicates), and histological score (L) (n = 5 biological replicates) for rat coccygeal IVDs. Data are presented as the mean ± SEM. At least 3 independent experiments were performed. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA (J–L).