The functional and pathologic relevance of autophagy proteases
Álvaro F. Fernández, Carlos López-Otín
Álvaro F. Fernández, Carlos López-Otín
Published January 2, 2015
Citation Information: J Clin Invest. 2015;125(1):33-41. https://doi.org/10.1172/JCI73940.
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Review

The functional and pathologic relevance of autophagy proteases

Abstract

Autophagy is a well-conserved catabolic process essential for cellular homeostasis. First described in yeast as an adaptive response to starvation, this pathway is also present in higher eukaryotes, where it is triggered by stress signals such as damaged organelles or pathogen infection. Autophagy is characterized at the cellular level by the engulfment of portions of the cytoplasm in double-membrane structures called autophagosomes. Autophagosomes fuse with lysosomes, resulting in degradation of the inner autophagosomal membrane and luminal content. This process is coordinated by complex molecular systems, including the ATG8 ubiquitin–like conjugation system and the ATG4 cysteine proteases, which are implicated in the formation, elongation, and fusion of these autophagic vesicles. In this Review, we focus on the diverse functional roles of the autophagins, a protease family formed by the four mammalian orthologs of yeast Atg4. We also address the dysfunctional expression of these proteases in several pathologic conditions such as cancer and inflammation and discuss potential therapies based on their modulation.

Authors

Álvaro F. Fernández, Carlos López-Otín

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Figure 2

Roles and regulation of the ATG4 protease family.

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Roles and regulation of the ATG4 protease family. The complexity of the ...
The complexity of the mammalian ATG8 protein system is reflected in the substrate specificity of ATG4 proteases and their particular roles. Besides the autophagic response, all ATG4 proteases have been involved in cancer, and defects in ATG4A, ATG4B, and ATG4D are also linked to intestinal disorders. Variants of ATG4C have been identified in aging free of major diseases, and ATG4D might be essential in the crosstalk between autophagy and apoptosis and is required for correct mitophagy during erythropoiesis. ATG4B has been widely described as necessary for the proper function of secretory cells. These proteases must be finely controlled by different regulators to coordinate this wide range of functions. Thus transcription factors such as p53, FOXO3, EGR11, or C/EBPb and several microRNAs such as miR-101, miR-376b, and miR-34a are responsible for the modulation of Atg4 genes. Additionally, ATG4 proteases can also be posttranslationally regulated by ROS-dependent oxidation or by E3 ubiquitin ligases such as RNF5.