Atg4b is a core protein belonging to the autophagy-related cysteine protein family. It is essential for cleaving precursor MAP1LC3/LC3 or deconjugating lipidated LC3-II, thus driving autophagosome formation, and plays a crucial role in the autophagy pathway [1,2,5]. Autophagy is a key process in eliminating and recycling cellular components in response to stress, and Atg4b's function is vital for maintaining cellular homeostasis. Genetic models, such as gene knockout mouse models, can be used to study its functions in vivo.

In a study, a new E3 ligase of Atg4b, UBE3C, was identified. UBE3C assembles K33-branched ubiquitin chains on Atg4b at Lys119 without causing its degradation. UBE3C-induced increased ubiquitination of Atg4b inhibits autophagy flux, likely due to reduced Atg4b activity and its interaction with LC3, and this can be reversed by mutating lysine 119 of Atg4b to arginine. Under starvation, the interaction between Atg4b and UBE3C decreases, removing the K33-branched ubiquitin chain [1]. miR-34c-5p was found to target Atg4b, reducing its expression, suppressing autophagic flux in cardiomyocytes, and contributing to isoprenaline-induced cardiac hypertrophy [3]. Also, circ-0000953 deficiency exacerbates podocyte injury and autophagy disorder by targeting Mir665-3p-Atg4b in diabetic nephropathy [4].

In conclusion, Atg4b is essential for autophagy, with its activity regulated by post-translational modifications like ubiquitination. Research using gene-related models has revealed its significance in diseases such as cardiac hypertrophy and diabetic nephropathy. Understanding Atg4b's functions provides insights into the autophagy mechanism and potential therapeutic targets for related diseases.

References:

1. Sun, Chaonan, Chen, Yuxin, Gu, Qianqian, Liu, Peiqing, Li, Min. 2024. UBE3C tunes autophagy via ATG4B ubiquitination. In Autophagy, 20, 645-658. doi:10.1080/15548627.2023.2299514. https://pubmed.ncbi.nlm.nih.gov/38146933/

2. Yang, Gaoxia, Li, Yang, Zhao, Yuqian, Liu, Bo, Liu, Jie. 2020. Targeting Atg4B for cancer therapy: Chemical mediators. In European journal of medicinal chemistry, 209, 112917. doi:10.1016/j.ejmech.2020.112917. https://pubmed.ncbi.nlm.nih.gov/33077263/

3. Zhang, Yuhong, Ding, Yanqing, Li, Min, Ye, Jiantao, Liu, Peiqing. 2021. MicroRNA-34c-5p provokes isoprenaline-induced cardiac hypertrophy by modulating autophagy via targeting ATG4B. In Acta pharmaceutica Sinica. B, 12, 2374-2390. doi:10.1016/j.apsb.2021.09.020. https://pubmed.ncbi.nlm.nih.gov/35646533/

4. Liu, Xueqi, Jiang, Ling, Zeng, Hanxu, Qi, Xiangming, Wu, Yonggui. 2023. Circ-0000953 deficiency exacerbates podocyte injury and autophagy disorder by targeting Mir665-3p-Atg4b in diabetic nephropathy. In Autophagy, 20, 1072-1097. doi:10.1080/15548627.2023.2286128. https://pubmed.ncbi.nlm.nih.gov/38050963/

5. Park, Na Yeon, Jo, Doo Sin, Cho, Dong-Hyung. 2022. Post-Translational Modifications of ATG4B in the Regulation of Autophagy. In Cells, 11, . doi:10.3390/cells11081330. https://pubmed.ncbi.nlm.nih.gov/35456009/