ATG4B

Description

The ATG4B (autophagy related 4B cysteine peptidase) is a protein-coding gene located on chromosome 2.

ATG4B is an enzyme that in humans is encoded by the ATG4B gene. 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 encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. One main function of Atg4 is to cleave the pre-protein of Atg8, leading to the non-lipidated soluble (-I) form which can be processed further by Atg3, Atg7, Atg5-12 into the lipidated form (-II) anchored to the autophagic membrane. ATG4B has been shown to interact with GABARAPL2.

ATG4B, also known as AUT-like 1 cysteine endopeptidase, Autophagy-related cysteine endopeptidase 1, or Autophagy-related protein 4 homolog B, is a cysteine protease that plays a crucial role in autophagy. It mediates both proteolytic activation and delipidation of ATG8 family proteins, which are essential for the formation of autophagosomes, the cellular structures responsible for engulfing and degrading damaged cellular components. ATG4B is required for canonical autophagy (macroautophagy), non-canonical autophagy, and mitophagy, a specialized form of autophagy that targets mitochondria. ATG4B's protease activity is essential for activating ATG8 proteins by cleaving their C-terminal amino acid, revealing a C-terminal glycine. This glycine is crucial for the conjugation of ATG8 proteins to phosphatidylethanolamine (PE) and their insertion into membranes, which is necessary for autophagy. ATG4B also acts as a deubiquitinating-like enzyme, removing ATG8 conjugated to other proteins, such as ATG3, counteracting the formation of high-molecular weight conjugates. In addition to its protease activity, ATG4B also mediates the delipidation of ATG8 family proteins, removing PE from ATG8 proteins during macroautophagy. ATG4B also plays a role in non-canonical autophagy, catalyzing the delipidation of ATG8 proteins conjugated to phosphatidylserine (PS) at endolysosomal compartments. Compared to other ATG4 family members (ATG4A and ATG4C), ATG4B is the primary protein for proteolytic activation of ATG8 proteins, while exhibiting weaker delipidation activity than other ATG4 paralogs. Interestingly, ATG4B is involved in phagophore growth during mitophagy, independent 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.

ATG4B is also known as APG4B, AUTL1, HsAPG4B.

Associated Diseases

WES Whole Exome Sequencing