A circular RNA produced by LRBA promotes cirrhotic mouse liver regeneration through facilitating the ubiquitination degradation of p27.

Liangliang Xu, Jinfu Zhang, Li Li, Peng Wang, Xiaobo Zheng, Jianchen Luo, Shuqi Zhang, Lian Li, Pengsheng Yi, Yanfang Zhang, Tao Yan, Liang Xie, Lei Feng, Ming Zhang, Mingqing Xu

Liver international : official journal of the International Association for the Study of the Liver 2023 Jul

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Accumulating circular RNAs (circRNAs) play important roles in tissue repair and organ regeneration. However, the biological effects of circRNAs on liver regeneration remain largely unknown. This study aims to systematically elucidate the functions and mechanisms of circRNAs derived from lipopolysaccharide-responsive beige-like anchor protein (LRBA) in regulating liver regeneration. CircRNAs derived from mouse LRBA gene were identified using CircBase. In vivo and in vitro experiments were conducted to confirm the effects of circLRBA on liver regeneration. RNA pull-down and RNA immunoprecipitation assays were used to investigate the underlying mechanisms. Clinical samples and cirrhotic mouse models were used to evaluate the clinical significance and transitional value of circLRBA. Eight circRNAs derived from LRBA were registered in CircBase. The circRNA mmu_circ_0018031 (circLRBA) was significantly upregulated in the liver tissues after 2/3 partial hepatectomy (PHx). Adeno-associated virus serotype 8 (AAV8)-mediated knockdown of circLRBA markedly inhibited mouse liver regeneration after 2/3 PHx. In vitro experiments confirmed that circLRBA exerted its growth-promoting function mainly through liver parenchymal cells. Mechanistically, circLRBA acted as a scaffold for the interaction between E3 ubiquitin-protein ligase ring finger protein 123 and p27, facilitating the ubiquitination degradation of p27. Clinically, circLRBA was lowly expressed in cirrhotic liver tissues and negatively correlated with perioperative levels of total bilirubin. Furthermore, overexpression of circLRBA enhanced cirrhotic mouse liver regeneration after 2/3 PHx. We conclude that circLRBA is a novel growth promoter in liver regeneration and a potential therapeutic target related to deficiency of cirrhotic liver regeneration. © 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Citation

Liangliang Xu, Jinfu Zhang, Li Li, Peng Wang, Xiaobo Zheng, Jianchen Luo, Shuqi Zhang, Lian Li, Pengsheng Yi, Yanfang Zhang, Tao Yan, Liang Xie, Lei Feng, Ming Zhang, Mingqing Xu. A circular RNA produced by LRBA promotes cirrhotic mouse liver regeneration through facilitating the ubiquitination degradation of p27. Liver international : official journal of the International Association for the Study of the Liver. 2023 Jul;43(7):1558-1576