Overview
Our lab aims to understand—at the molecular, cellular, and organismal levels—how protein unfolding in the endoplasmic reticulum (ER) causes human disease, in order to develop new therapeutic approaches for these conditions.
Summary
An ER intracellular signaling pathway called the unfolded protein response (UPR) ensures that the machinery needed to fold and assemble secreted and membrane proteins is sufficient to meet cellular secretory needs. When the ER's protein folding needs outweigh its capacity to sustain the protein folding process, cells experience a distinct form of stress—"ER stress"— that triggers the UPR pathway. UPR outputs initially reduce ER stress through augmenting the levels of ER-resident chaperones and protein modification enzymatic activities; these outputs are conserved in all eukaryotes. However, if ER stress cannot be alleviated through these adaptive outputs, in higher eukaryotes such as mammals, the UPR triggers a diametrically opposite strategy to instead promote destructive outcomes, including sterile inflammation, dedifferentiation, and ultimately programmed cell death (Molecular Cell, 69(2), 2018).
Over the last 15 years, our lab was the first to elucidate how such a pivotal ER stress-induced life-death switch is controlled in mammalian cells by the master UPR sensor/effector, IRE1alpha, an ER trans-membrane bifunctional kinase/RNAse protein. While several other labs have defined the adaptive benefits proceeding through IRE1alpha, our lab was the first to show that IRE1alpha has alternative outputs—both adaptive and destructive—depending on the strength of upstream stresses; these “Janus-faced” distinctions of IRE1 function are key to shaping therapy. For instance, in 2009, we were the first to find that IRE1alpha has alternate RNAse outputs that are controlled by its kinase domain to promote divergent cell fates under ER stress (Cell, 138, 562–575, 2009). In that study we showed that hyperactivated IRE1alpha caused the ER-localized degradation of myriad mRNAs—including those encoding ER chaperones—in mammalian cells and the consequent depletion of these mRNAs leads mammalian cells to enter apoptosis. Then in 2012 we identified a critical node in the UPR called the thioredoxin-interacting protein (TXNIP), which promotes sterile inflammation in pancreatic islet beta cells to cause development of diabetes (Cell Metabolism, 16(2): 250-64 (2012).