In order for the cell to respond to changing demands (e.g. energy supply and environmental factors), but also to replace old and damaged organelles, each cell is capable of autophagy. This occurs via the formation of the autophagosome, from an isolation membrane, and its fusion with a lysosome.¹ The endoplasmic reticulum (ER) is the largest intracellular endomembrane system and can be classed as the “protein machinery” of the cell.² As the location of synthesis of surface-bound or excretory proteins, the ER is also responsible for the folding of these proteins into their tertiary structure. Proteins that are incorrectly or insufficiently folded are extracted and degraded (ER associated degradation (ERAD)).³ Disruption of ER function often leads to an accumulation of unfolded proteins, known as ER stress. If this occurs, the cell activates the unfolded protein response (UPR) to restore homeostasis and ensure cell survival.^3–5 Persistent ER stress has been linked to several diseases such as diabetes, neurodegenerative disorders, cancer, but also inflammatory bowel diseases (IBD) such as Crohn’s Disease (CD) or Ulcerative Colitis (UC).^3,6,7 Other than protein synthesis, the ER also plays a vital part in lipid synthesis and ion homeostasis.² As such, the ER is subject to constant turnover to replace old and/or damaged ER, as well as being used as a source of energy (by proteolysis) during longer periods of hunger.⁸ Several ER-phagy receptors have been discovered in the past years, such as cell-cycle progression gene 1 (CCPG1) and reticulon 3 (RTN3).⁹

A mutation resulting in a loss-of-function of autophagy related 16-like 1 (ATG16L1 – a known risk gene for IBD) is associated with deregulation of ER function, as well as defective autophagy. ATG16L1 loss resulted in unrestricted IL-22 dependent IFN-I expression via cyclic guanoadenine synthase coupled with stimulator of IFN genes (cGAS-STING) (STING is coded for by TMEM173) dependent detection of cytosolic dsDNA.^10,11 This excessive IFN-I response resulted in massive necroptosis in the intestinal epithelium when autophagy is impaired, e.g. in ATG16L1 deficiency, and thus promoted intestinal inflammation.¹¹ As ER-phagy plays a role in both autophagy and ER-function, it is plausible that ER stress exacerbates in the situation of defective ER-phagy. This could mean that ER-phagy receptors may play a role in the IFN-I response, which has been shown to be dependent on ER-phagy.¹² Autophagy defects and unresolved ER stress mostly affect secretory highly active cells, e.g. Paneth and goblet cells¹³, meaning that loss of an ER-phagy protein could disrupt cellular homeostasis, inducing cell death and subsequent inflammatory phenotypes.

Chronic inflammatory diseases are immune-related disorders with severe morbidity, which can only be ameliorated but generally not cured by life-long therapies, posing a major economic challenge to public health. IBD is an archetypic model for the interplay of environmental triggers (as nutrition, infections and toxic agents) and genetic factors, which regulate immune signals and epithelial integrity. A link between ER-phagy and IBD has not yet been discovered.