ATG4D
Description
The ATG4D (autophagy related 4D cysteine peptidase) is a protein-coding gene located on chromosome 19.
The human ATG4D gene encodes the protein Autophagy related 4D, cysteine peptidase. Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene belongs to the autophagy-related protein 4 (Atg4) family of C54 endopeptidases. Members of this family encode proteins that play a role in the biogenesis of autophagosomes, which sequester the cytosol and organelles for degradation by lysosomes. Alternative splicing results in multiple transcript variants.
ATG4D is a cysteine protease that plays a crucial role in autophagy by performing both proteolytic activation and delipidation of ATG8 family proteins. Its protease activity is essential for activating ATG8 family proteins by cleaving the C-terminal amino acid of ATG8 proteins like MAP1LC3 and GABARAPL2, exposing a C-terminal glycine. This glycine exposure is crucial for the conjugation of ATG8 proteins to phosphatidylethanolamine (PE) and their insertion into membranes, which are essential for autophagy. ATG4D also mediates the delipidation of ATG8 family proteins. It catalyzes the delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy. ATG4D participates in non-canonical autophagy, a pathway where ATG8 proteins are conjugated to single membranes at endolysosomal compartments. This involves catalyzing the delipidation of ATG8 proteins conjugated to phosphatidylserine (PS). ATG4D is implicated in maintaining neuronal homeostasis in the central nervous system through autophagy. Compared to other members of the ATG4 family (ATG4A, ATG4B, or ATG4C), ATG4D exhibits the most significant delipidation activity while displaying weak proteolytic activation of ATG8 proteins. ATG4D is involved in phagophore growth during mitophagy independently of its protease activity and ATG8 proteins. It regulates ATG9A trafficking to mitochondria and facilitates phagophore-endoplasmic reticulum contacts during the lipid transfer phase of mitophagy. ATG4D functions as an autophagy regulator that connects mitochondrial dysfunction with apoptosis. The mitochondrial import of ATG4D during cellular stress and differentiation may play significant roles in regulating mitochondrial physiology, ROS production, mitophagy, and cell viability.
ATG4D is also known as APG4-D, APG4D, AUTL4, HsAPG4D.
