Investigating a potential oncogenic role for
AGR2 in pro-survival autophagy

Abstract

Members of the Protein Disulphide Isomerase (PDI) family have essential roles in mediating the oxidation, reduction and isomerisation of disulphide bonds during protein maturation in the endoplasmic reticulum. PDI family members are characterised by the presence of a thioredoxin motif (CXXC) with dual cysteines that permit proteins their oxidoreductase activity. However, PDI proteins that harbour evolutionary divergent thioredoxin motifs have also been identified; the Anterior Gradient-2 (AGR2) protein that possesses a single cysteine residue in its thioredoxin-like domain (CPHS) is one such protein. AGR2 is known to be required for the correct folding and secretion of mucins, the primary gel-forming proteins within mucus. Although its expression is normally restricted to certain secretory and reproductive organs, AGR2 is found derepressed in various cancers. We have previously shown that AGR2 forms a disulphide-dependent interaction with the autophagy receptor Sequestosome 1 (SQSTM1). The oxidation of SQSTM1 is required for the stimulation of autophagy to promote cell survival under conditions of oxidative and proteotoxic stress. The disulphide-dependent interaction between AGR2 and SQSTM1 links AGR2 to autophagy for the first time. Tumours are exposed to high levels of oxidative stress, and thus autophagy can prevent cytotoxicity by removing the cellular components damaged by oxidative stress that may otherwise be toxic to the cell. It is plausible, therefore, that the upregulation of SQSTM1 and AGR2 in human cancers could be involved in the induction of pro-survival autophagy.