<i>mir-233</i> Modulates the Unfolded Protein Response in <i>C. elegans</i> during <i>Pseudomonas aeruginosa</i> Infection

<div><p>The unfolded protein response (UPR), which is activated by perturbations of the endoplasmic reticulum homeostasis, has been shown to play an important role in innate immunity and inflammation. However, little is known about the molecular mechanisms underlying activation of the UPR during immune responses. Using small RNA deep sequencing and reverse genetic analysis, we show that the microRNA <i>mir-233</i> is required for activation of the UPR in <i>Caenorhabditis elegans</i> exposed to <i>Pseudomonas aeruginosa</i> PA14. <i>P. aeruginosa</i> infection up-regulates the expression of <i>mir-233</i> in a p38 MAPK-dependent manner. Quantitative proteomic analysis identifies SCA-1, a <i>C. elegans</i> homologue of the sarco/endoplasmic reticulum Ca²⁺-ATPase, as a target of <i>mir-233</i>. During <i>P. aeruginosa</i> PA14 infection, <i>mir-233</i> represses the protein levels of SCA-1, which in turn leads to activation of the UPR. Whereas <i>mir-233</i> mutants are more sensitive to <i>P. aeruginosa</i> infection, knockdown of <i>sca-1</i> leads to enhanced resistance to the killing by <i>P. aeruginosa</i>. Our study indicates that microRNA-dependent pathways may have an impact on innate immunity by activating the UPR.</p>