ATG7

ATG7 Full Name

autophagy related 7

ATG7 Introduction

ATG7 is an upstream regulatory factor for the autophagy pathway in cells. The primary function of ATG7 is to serve as the E1-like activating enzyme for the ATG12-ATG5 conjugation system and ATG8-phosphatidylethanolamine (PE) conjugation system, which are ubiquitin-like conjugation systems. ATG7 activates ATG12 and ATG8 in an ATP-dependent manner, and uses the energy released during ATP hydrolysis to form a high-energy thioester bond between ATG12 or ATG8 and the active site Cys572 of ATG7, and then transfers the activated ATG12 to the E2-like enzyme ATG10 which ultimately covalently binds to ATG5 in the presence of ATG16L1 to form ATG12-ATG5-ATG16L1 complex. In a parallel process, the activated ATG8 is transferred to the E2-like enzyme ATG3, and ultimately, in the presence of the E3-like enzyme activity of ATG12-ATG5-ATG16L1, covalently binds to phosphatidylethanolamine (PE) on the autophagosome membrane to form ATG8-PE (i.e. LC3-II). The entire series of reactions is an essential step in the autophagosome membrane extension reaction and final closure to form the double-membrane vesicle autophagosome. As a result, the functional status of ATG7 ultimately determines the efficiency of the entire autophagic flux. The human ATG7 protein has a monomer length of about 703 amino acids, with a molecular weight of about 78 kDa. It forms a homodimer in function, with its N-terminal domain (NTD) mainly responsible for interaction with the E2-like enzyme ATG3 and its C-terminal domain (CTD) mainly responsible for substrate recognition and binding of ATG8. This highly precise structural division of the enzyme function endows it with reaction specificity.

Figure 1. ATG7 drives the fundamental stages of degradative autophagy. (Source: Collier JJ, et al. 2021)

ATG7 is best known for its essential role in autophagy, which is required for quality control and homeostasis at the cellular level. ATG7-mediated autophagy, by degrading aged organelles (e.g., mitochondria), misfolded/aggregated proteins and invading pathogens, plays a critical role in cell survival in response to a variety of stress stimuli, including nutrient deprivation, oxidative stress, hypoxia, and infection. However, the functions of ATG7 are not restricted to autophagy. It has been found to be broadly engaged in many non-autophagy-dependent biological processes. For instance, ATG7 can control the progression of the cell cycle and cell cycle arrest can be caused by ATG7 deficiency, which is at least partly due to its control of the p53 signaling pathway. In addition, ATG7 is known to be critically involved in maintaining the functionality and survival of certain types of cells. These roles include protection of neurons against degenerative changes, preservation of the self-renewal capacity of hematopoietic stem cells, and regulation of adipocyte differentiation. ATG7 also serves non-autophagic functions in the cellular defense against pathogen infection. One example is the promotion of phagosome-lysosome fusion through a process termed "LC3-associated phagocytosis" for the efficient clearance of invading bacteria.

Loss of ATG7 activity is a major cause of some human diseases. In neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis, defective autophagy has been hypothesized to be a principal reason for disease-associated toxic protein aggregation and neuronal cell death. Autophagy mediated by ATG7 is required for the clearance of these disease-associated abnormal proteins (e.g. β-amyloid, tau protein and α-synuclein). In mice, neuron-specific deletion of Atg7 resulted in massive intraneuronal accumulation of ubiquitinated inclusions with progressive neuronal loss and behavioral abnormalities.

Alternate Names for ATG7

ATG7; autophagy related 7; GSA7; APG7L; APG7-LIKE; ubiquitin-like modifier-activating enzyme ATG7; hAGP7; autophagy-related protein 7; ATG12-activating enzyme E1 ATG7; ATG7 autophagy related 7 homolog; ubiquitin activating enzyme E1-like protein; ubiquitin-activating enzyme E1-like protein;

• 1. Collier JJ, et al. Emerging roles of ATG7 in human health and disease. EMBO Mol Med. 2021 Dec 7;13(12):e14824.
  2. Xiong J. Atg7 in development and disease: panacea or Pandora's Box? Protein Cell. 2015 Oct;6(10):722-34.