Atg4B, a member of the autophagy-related cysteine protein family, is essential for autophagy. It cleaves precursor MAP1LC3/LC3 or deconjugates lipidated LC3-II, driving autophagosome formation. Autophagy is a crucial process for eliminating and recycling cellular components, and Atg4B is thus vital in maintaining cellular homeostasis. Genetic models, such as KO or CKO mouse models, can significantly contribute to understanding its functions [1,2,5].

In a study, a new E3 ligase of Atg4B, UBE3C, was identified. UBE3C assembles K33-branched ubiquitin chains on Atg4B at Lys119, inhibiting autophagy flux without causing Atg4B degradation. Under starvation, the interaction between Atg4B and UBE3C decreases, removing the K33-branched ubiquitin chain. This shows that starvation-induced autophagy can be regulated by Atg4B ubiquitination [1]. In cardiac hypertrophy, miR-34c-5p targets Atg4B, reducing its expression, suppressing autophagic flux, and contributing to hypertrophy. Inhibiting miR-34c-5p restores Atg4B and increases autophagy [3]. Also, circ-0000953 deficiency exacerbates podocyte injury and autophagy disorder by targeting Mir665-3p-Atg4b in diabetic nephropathy, and overexpression of Atg4b recovers podocyte autophagy [4].

In conclusion, Atg4B plays a key role in autophagy, influencing various biological processes and disease conditions. Model-based research, especially KO/CKO mouse models, has provided insights into its functions in diseases like cardiac hypertrophy and diabetic nephropathy, highlighting its potential as a therapeutic target.