Macroautophagy (autophagy) is an evolutionarily conserved and dynamic degradation/recycling pathway in which portions of the cytoplasm, such as dysfunctional
proteins and surplus organelles, are engulfed by double-membrane bound vesicles through a lysosome-dependent process. As the only
proteolytic enzyme of the core mammalian autophagy
proteins, autophagy-related protein 4 (ATG4) primes newly synthesized pro-light chain 3 (LC3) to form LC3-I that attaches to
phosphatidylethanolamine and delipidates LC3-PE to LC3-I for recycling. Besides autophagy, ATG4 has been shown to be involved in regulating various biological and
pathological processes. The roles of ATG4 in
cancer therapy, a methodology for ATG4 activity detection, and the discovery of chemical modulators have been well-reviewed. However, a comprehensive summary on how ATG4 is regulated by multiple factors and, thereby, how ATG4 influences autophagy or other pathways remains lacking. In this paper, we summarize multiple processes and molecules that regulate the activity of ATG4, such as micro-RNAs, posttranslational modifications, and small molecules. Additionally, we focus on the relationship between ATG4 and diverse diseases, including
cancer, neurodegeneration, microbial
infection, and other diseases. It provides insight regarding potential ATG4-targeted therapeutic opportunities, which could be beneficial for future studies and human health.