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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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 3

Replicative senescence triggers the inflammatory senescence phenotype acquisition of NP cells during IVDD progression.

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Replicative senescence triggers the inflammatory senescence phenotype ac...
(A) GSEA showing enrichment of “replicative senescence” in degenerated NP tissues. (B) Relative telomere lengths of isolated NP cells from human NP tissues with different Pfirrmann degenerative grades (n = 24). (C) Correlation analysis between relative telomere length and Pfirrmann degenerative grades (n = 24). (D) Relative telomere lengths from age- and sex-matched case pairs of NP tissues (n = 20). (E) Differential heatmap of the SASP in NP cells (n = 4 biological replicates). (F) Change pathways of transcriptional profiles enriched in P8 NP cells compared with P2 NP cells (n = 3 biological replicates). (G) Correlation analysis of differential transcriptional profiles in cultured NP cells (y axis) compared with those in isolated NP cells from human NP tissues (x axis). (H) Representative Western blots of p-p53, p21, and p16 levels in NP cells (n = 4 biological replicates). (I) Representative Western blots of γH2A, and 53BP levels in NP cells (n = 4 biological replicates). (J) IF staining of γH2A foci in NP cells. Scale bars: 10 μm. Data are presented as the median ± IQR or the mean ± SEM. At least 3 independent experiments were performed. *P < 0.05, **P < 0.01, by permutation test (A), rank-sum test (B), paired Student’s t test (D), and simple linear regression (C and G).