ATG4A
Description
The ATG4A (autophagy related 4A cysteine peptidase) is a protein-coding gene located on chromosome X.
ATG4A is an enzyme encoded by the ATG4A gene in humans. It is a cysteine protease that plays a crucial role in autophagy, a cellular process that degrades intracellular proteins and damaged organelles. Autophagy is essential for cell homeostasis, remodelling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced autophagy levels have been observed in some malignant tumors, suggesting a role in regulating uncontrolled cell growth associated with cancer. ATG4A belongs to the autophagin protein family and the C-54 family of cysteine proteases. Different isoforms of ATG4A are encoded by transcript variants.
ATG4A is a cysteine protease that plays a crucial role in autophagy. It mediates both proteolytic activation and delipidation of ATG8 family proteins. Its protease activity is essential for the proteolytic activation of ATG8 proteins, cleaving the C-terminal amino acid to expose a glycine residue. This exposed glycine is critical for ATG8 protein conjugation to phosphatidylethanolamine (PE) and subsequent membrane insertion, which is necessary for autophagy. ATG4A has a preference for substrates like GABARAPL2, followed by MAP1LC3A and GABARAP. Furthermore, ATG4A acts as a deubiquitinating-like enzyme, counteracting the formation of high-molecular weight conjugates of ATG8 proteins. It removes ATG8 conjugated to other proteins, such as ATG3. In addition to its protease activity, ATG4A also mediates delipidation of ATG8 family proteins, catalyzing the delipidation of PE-conjugated forms during macroautophagy. Compared to ATG4B, the primary protein involved in the proteolytic activation of ATG8 proteins, ATG4A exhibits weaker cleavage activity but stronger delipidation activity. Interestingly, ATG4A is involved in phagophore growth during mitophagy independently of its protease activity and ATG8 proteins. It regulates ATG9A trafficking to mitochondria and promotes phagophore-endoplasmic reticulum contacts during the lipid transfer phase of mitophagy.
ATG4A is also known as APG4A, AUTL2, HsAPG4A.
Associated Diseases
- X-linked Alport syndrome
- ghosal hematodiaphyseal dysplasia
- neutropenia, severe congenital, 1, autosomal dominant
- cancer
- osteoarthritis
- microphthalmia with limb anomalies
- pancreatic ductal adenocarcinoma
- breast cancer
