Pancreatic beta cell death marks a critical turning point in the development of diabetes. In type 1 diabetes, a combination of cytokines trigger beta cell inflammation ultimately leading to beta cell apoptosis. The Tribbles-family of pseudokinases have been strongly implicated in the regulation of inflammatory pathways. We have focused our research efforts on understanding signaling mechanisms that modulate the progression of beta cell inflammation and found that the pseudokinase TRB3 plays a key role in augmenting mechanisms that lead to cell death. We find that in addition to its role in ER stress, TRB3 is contributes to compromise in mitochondrial quality control and integrity. Both mechanisms together likely contribute to susceptibility of beta cell to proapoptotic stimuli. In this application, we will further define examine molecular mechanisms that enable TRB3-mediated fine tuning of beta cell survival and death. We propose the following specific aims: 1) Examine how mice with whole body and beta cell-specific loss of TRB3, response to induced diabetes. 2) Examine the role of TRB3 interacting proteins in augmenting inflammation. 3) Explore the role of TRB3 in ER-mitochondrial crosstalk.