IGF2BP3 modified GLI2 transcriptionally regulates SYVN1 and facilitates sepsis liver injury through autophagy

Autophagy enhancement in septic liver injury can play a protective role. Nerveless, the mechanism of autophagy-mediated septic liver injury needs further investigation. Our study demonstrated that in septic condition, GLI Family Zinc Finger 2 (GLI2) was elevated, whereas peroxisome-proliferator-acti...

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Published in:iScience 2024-06, Vol.27 (6), p.109870-109870, Article 109870
Main Authors: Sun, Chuanzheng, Gao, Min, Hu, Haotian, Qi, Jing, Tang, Yishu, Cao, Xiaoxue, Zhang, Runbang, Liu, Huaizheng
Format: Article
Language:English
Subjects:
cell biology
hepatology
immunology
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Summary:Autophagy enhancement in septic liver injury can play a protective role. Nerveless, the mechanism of autophagy-mediated septic liver injury needs further investigation. Our study demonstrated that in septic condition, GLI Family Zinc Finger 2 (GLI2) was elevated, whereas peroxisome-proliferator-activated receptor α (PPARα) was downregulated. Suppressing GLI2 or synovialapoptosis inhibitor 1 (SYVN1) in LPS-exposed cells increased PPARα levels, enhanced cell viability and autophagy, while inhibiting apoptosis. LPS enhanced the GLI2-SYVN1 promoter binding. SYVN1 fostered ubiquitin-mediated degradation of PPARα. IGF2BP3 stabilized GLI2 mRNA by targeting its m6A site. Silencing IGF2BP3 led to decreased GLI2 and SYVN1 but increased PPARα levels, promoting cell survival and autophagy, while repressing apoptosis. This was counteracted by SYVN1 overexpression. In cecal ligation and puncture mice, IGF2BP3, SYVN1, or GLI2 knockdown ameliorated liver damage and augmented autophagy. In summary, IGF2BP3 enhanced GLI2 stability, overexpressed GLI2 subsequent promoted SYVN1 levels by interacting with its promoter, leading to ubiquitinated degradation of PPARα, thereby inhibiting PPARα-mediated autophagy and then exacerbating liver injury in sepsis. [Display omitted] •Knockdown of GLI2, SYVN1, or IGF2BP3 promoted PPARα-mediated autophagy•GLI2 promoted the ubiquitination degradation of PPARα via SYVN1•IGF2BP3 recognized the m6A site of GLI2 and increased its mRNA stability•IGF2BP3/SYVN1 silence promoted autophagy and improved septic liver injury in vivo Immunology; Hepatology; Cell biology
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2024.109870