Annexin A2 regulates unfolded protein response via IRE1-XBP1 axis in macrophages during P. aeruginosa infection

Pseudomonas aeruginosa is a severe Gram-negative opportunistic bacterium that causes a spectrum of organ system diseases, particularly in immunocompromised patients. This bacterium has been shown to induce unfolded protein response (UPR) during mammalian infection. Annexin A2 (AnxA2) is a multicompartmental protein relating to a number of cellular processes; however, it remains unknown whether AnxA2 coordinates a UPR pathway under bacterial infection conditions. Here, we report that the endoplasmic reticulum stress inositol-requiring enzyme 1 (IRE1)-X-box binding protein 1 (XBP1) pathway was up-regulated by AnxA2 through p38 MAPK signaling following P. aeruginosa infection in macrophages, whereas ATF4 and ATF6 not. In addition, XBP1 was found as a positive regulator of innate immunity to tame P. aeruginosa challenges by enhancing autophagy and bacterial clearance. XBP1 also facilitated NF-kappa B activation to elicit the release of proinflammatory cytokines predominantly in macrophages. Together, our findings identify AnxA2 as a regulator for XBP1-mediated UPR pathway.

Automated summary

This study found that AnxA2 up-regulates the IRE1-XBP1 pathway through p38 MAPK signaling in macrophages infected with P. aeruginosa. XBP1 acts as a positive regulator of innate immunity, enhances autophagy and bacterial clearance, and facilitates NF-kappa B activation to release proinflammatory cytokines mainly in macrophages. These findings identify AnxA2 as a regulator for the XBP1-mediated UPR pathway.