The endoplasmic reticulum (ER) serves many general functions, including the facilitation of protein folding and the transport of synthesized proteins, but it also has an important and more specialized role in sensing cellular stress. ER-stress identifies a group of signals that induce a transcriptional program enabling cells to survive protein overload and injury in the ER. This highly coordinated response involves three parallel signaling branches localized at the ER, namely IRE1, ATF6 and PERK.New findings suggest that these signaling pathways may regulate cellular processes independently of the ER-stress response. We have previously shown that some innate immune receptors such as Toll-like receptors specifically activate the IRE1 signaling pathway to enhance cytokine production. However, this is an emerging field of research and little is known on the specific nature of ER-signaling pathways and their function in regulating pathways in absence of a classical ER-stress response.The longterm goals of this proposal are to elucidate the molecular mechanisms and pathways emerging from the ER and regulating innate immune responses, and to address the physiological role of specific ER-signaling pathways in inflammation. Three complementary research sub-projects were designed. The first sub-project will identify and characterize compounds and conditions that trigger specific ER-signaling pathways. The second sub-project focuses on the biochemical characterization of signaling pathways emerging from the ER-associated kinases IRE1 and PERK. The third sub-project is aimed at investigating mechanisms by which ER-signaling pathways affect innate immune and inflammatory responses.The knowledge gained from this study will provide a better understanding of the mechanisms by which the ER and the cytosol interact to orchestrate physiological responses that help the organism to cope with infections and pathogenic insults.