circGlis3 promotes β-cell dysfunction by inhibiting hnRNPF nuclear translocation and encoding a novel Glis3-348aa protein

Published: 11 October 2023| Version 1 | DOI: 10.17632/zt9z3txm54.1
Li Xiong


Summary Circular RNAs (circRNAs) are crucial regulators of β-cell function and are involved in lipotoxicity-induced β-cell damage in type 2 diabetes mellitus (T2DM). We previously identified that circGlis3, a circRNA derived from exon 4 of the diabetes susceptibility gene Glis3, was upregulated in lipotoxic β cells. However, the functional role and molecular mechanism of circGlis3 in β cells remain largely unknown. Here, we revealed that the splicing factor CUGBP Elav-Like Family Member 1 (CELF1) facilitated the biogenesis of circGlis3. Moreover, we established a transgenic mouse model and confirmed that specific overexpression of circGlis3 impaired β-cell function. Mechanistically, circGlis3 bound to heterogeneous nuclear ribonucleoprotein F (hnRNPF) and blocked its nuclear translocation, thereby reducing Sirt1 levels. Additionally, circGlis3 encoded a 348aa protein that interacted with GLIS3 and inhibited its transcriptional activity. Our data uncover a critical role of circGlis3 in β-cell dysfunction in T2DM, suggesting that circGlis3 may be a potential therapeutic target for T2DM. Keywords: Type 2 diabetes, β cells, Circular RNA, Protein coding, hnRNPF, Lipotoxicity



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