ATG4C

ATG4C Full Name

autophagy related 4C, cysteine peptidase

ATG4C Introduction

ATG4C (autophagy related 4C, cysteine peptidase) is a member of the ATG4 family of cysteine proteases, which are essential regulators of the autophagy machinery. For researchers investigating autophagy-related targets, ATG4C represents a critical but less extensively characterized component involved in the processing and recycling of ATG8 family proteins, including LC3 and GABARAP. ATG4C performs proteolytic cleavage of newly synthesized ATG8 proteins to expose the glycine residue required for lipid conjugation, enabling autophagosome membrane formation. It also participates in ATG8 delipidation, a process required for autophagosome maturation and efficient autophagic flux. Compared with other ATG4 family members, ATG4C exhibits distinct tissue-dependent functions, suggesting that it may regulate selective autophagy responses under specific physiological or pathological conditions.

The biological importance of ATG4C has been increasingly recognized through in vivo studies demonstrating its role in maintaining tissue homeostasis and stress adaptation. Genetic deletion of Atg4c in mice does not cause obvious developmental defects but results in impaired autophagy regulation in specific tissues, including reduced autophagic flux in skeletal muscle and diaphragm, leading to decreased exercise capacity and respiratory performance under nutrient stress conditions. ATG4C deficiency also affects immune system maintenance, with reduced peripheral T and B lymphocyte populations and increased accumulation of apoptotic cells in the spleen. These findings highlight ATG4C as a regulatory node connecting autophagy, cellular survival, and immune balance. In addition, ATG4C has been implicated in oxidative stress responses, where ROS-mediated AMPK activation can promote ATG4C regulation together with Beclin-1 to enhance autophagosome formation and autophagy-lysosome fusion, linking ATG4C activity to metabolic stress adaptation and vascular cell function.

Dysregulation of ATG4C has been associated with multiple disease contexts, particularly cancer and degenerative disorders where autophagy imbalance plays a central role. Genomic studies have identified recurrent ATG4C alterations in endometrial cancer, suggesting that impaired ATG4C-mediated autophagy may contribute to tumor development by disrupting cellular quality control mechanisms. In brain tumors, elevated ATG4C expression has been correlated with poor prognosis in patients with high-grade glioma, while ATG4C suppression has been reported to induce cell cycle arrest, promote apoptosis, and reduce tumor growth in experimental models. Beyond oncology, ATG4C may also participate in cardiovascular disease mechanisms through oxidative stress-related autophagy regulation, including pathways involved in vascular dysfunction and atherosclerotic plaque stability. Due to its dual role in maintaining normal autophagy and influencing disease-associated survival pathways, ATG4C is emerging as a potential target for studying autophagy-driven disorders and developing therapeutic strategies aimed at modulating cellular stress responses.

Alternate Names for ATG4C

ATG4C; autophagy related 4C, cysteine peptidase; APG4C; AUTL1; AUTL3; APG4-C; cysteine protease ATG4C; autophagin-3; APG4 autophagy 4 homolog C; AUT-like 3 cysteine endopeptidase

• 1.Tamargo-Gómez I, et al.; Analysis of ATG4C function in vivo. Autophagy. 2023, 19(11):2912-2933.
  2.Zhang Y, et al.; Transient receptor potential channels as key regulators of cell death in atherosclerosis. Front Immunol. 2025, 16:1661805.