Innate Immune Sensing of a Bacterial Protein in the ER of the Intestine by IRE1β

The plasma membrane and all membrane-bound organelles except for the Golgi and endoplasmic reticulum (ER) are equipped with pattern-recognition molecules to sense microbes or their products and induce innate immunity for host defense. Here, we report that Inositol-REquiring-1b (IRE1β) is activated to induce inflammation by Cholera Toxins (CT) as they co-opt the ER to cause disease. IRE1β is an isoform of IRE1α on the ER membrane, and only expressed in the intestinal epithelial cells. CT is the AB₅-subunit bacterial toxin family that transverse the Golgi and ER to gain access to the cytosol. In the ER, a fragment of the CT A-subunit (CTA) is unfolded, dissociated from the B-subunit, and retro-translocated to the cytosol to induce disease. To test if the ER can innately sense CT upon entry into the ER, we used mutant toxin lacking enzymatic activity on human intestinal CaCo2 cells or in vivo.

We found that IRE1β recognizes CTA to induce inflammation. This inflammatory response depends on the RNase activity of IRE1β implicating Regulated IRE1-Dependent Decay of mRNA in a novel innate immune mechanism of host defense originating from within the ER lumen of the intestine.

This discovery identifies a new general mechanism of host defense by some bacteria protein entering the ER to signal the host. The innate immune response induced by CTA depends on signal transduction by ER stress, which was recently identified as a risk factor for the development of inflammatory bowel disease and critically involved in sensing and affecting the gut microbiome.