Autophagy related 4D cysteine peptidase (ATG4D)

Autophagy related 4D cysteine peptidase (ATG4D) is a member of the autophagy-related protein 4 family of cysteine endopeptidases, and serves as a specialized enzyme that mediates the proteolytic processing and delipidation of ATG8 family proteins, including LC3 and GABARAP subtypes[1][2][3][4]. By cleaving the C-terminus of nascent ATG8 proteins to expose a glycine, ATG4D enables their subsequent conjugation to phospholipids (PE or PS), facilitating the formation and maturation of autophagosomes – the cellular structures responsible for degradation and recycling of cytosolic content. ATG4D is the principal enzyme responsible for delipidating ATG8 family proteins, allowing their recycling and maintenance of normal autophagic flux in mammalian cells. Loss of ATG4D results in marked changes in autophagosome dynamics, including increased numbers and reduced size, and has been causally linked to neurodegeneration and altered neuronal function in animal models. Emerging research connects genetic variations in ATG4D to human neurodevelopmental disorders, and these findings underscore its broader role in neurological health. While it does not have direct drug interactions yet, its centrality in autophagy makes it a relevant therapeutic target in cancer, neurodegeneration, and other diseases where cellular cleanup mechanisms are disrupted[1][2][3][4].

Other names

Cysteine protease ATG4DATG4D, mitochondrialAPG4DAUTL4Autophagin-4HsAPG4DAUT-like 4 cysteine endopeptidaseAutophagy-related cysteine endopeptidase 4Autophagy-related protein 4 homolog DSPGF101

For drugs modulating autophagy: inhibition or enhancement of lysosomal fusion, acidification, or flow may affect ATG4D-mediated processing of ATG8 family proteins. The mechanistic focus for ATG4D itself is proteolytic cleavage (exposes critical glycine for lipid conjugation) and delipidation (removal of PE/PS to recycle ATG8 proteins).