Sarah Bettigole, Ph.D.


One of the primary functions of the endoplasmic reticulum is to correctly fold and glycosylate nascent proteins.  When the intrinsic protein folding capacity is overwhelmed, as can happen under a variety of different stimuli, cells mount a coordinated response known as the unfolded protein response (UPR).  This response eliminates toxic levels of misfolded proteins by decreasing general protein translation while simultaneously increasing the overall protein folding capacity of the ER by selectively upregulating critical stress response protein chaperones, glycosylases, reductases, secretory pathway components and genes involved in endoplasmic reticulum biogenesis.

Accumulating evidence implicates the UPR in a variety of inflammatory diseases such as diabetes and rheumatoid arthritis, yet how the UPR and immune signaling pathways intersect is not well defined.  XBP-1 is the most highly conserved member of the UPR signaling pathway, and work from our lab and others have demonstrated pleiotropic and non-canonical roles for this transcription factor, such as in regulating organelle morphology, protein translation and secretion, lipid metabolism, and cellular differentiation.  Additionally, groundbreaking work by Hollien and Weissman (Science, 2006) revealed that the bifunctional kinase/RNAse IRE-1α can degrade a variety of cellular RNAs aside from its known role in cleaving XBP-1 mRNA.  Using a variety of Cre-Lox genetic mouse strains, disease models, bioinformatics analyses and in vitro cell culture approaches we aim to identify the non-canonical context- and cell type-specific functions of the IRE1/XBP1 signaling pathway in regulating the quality and magnitude of the inflammatory response in various immune cells.



ER Stress

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