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GRK 1482 Jahrbuch 2011-2014

Abstract Accumulation of unfolded proteins in the endoplasmic reticulum (ER) due to disturbances in protein homeostasis evokes the ER unfolded protein response (UPR). ER UPR involvement has been shown in many pathologies, including inflammatory bowel diseases. Activating transcription factor 6 (ATF6) is a key transcriptional activator of this signaling pathway. The aim of this dissertation is to investigate the effects of a constitutive activation of ATF6 and consequently ATF6 mediated ER UPR signaling on epithelial homeostasis, intestinal in- flammation, and tumorigenesis. Introduction Inflammatory bowel diseases (IBD) are immuno- logically mediated, spontaneously relapsing dis- orders which are associated with alterations in cellular stress signaling in intestinal epithelial cells (IEC). Unfolded protein responses (UPR) are stress signaling pathways important for the maintenance of organelle protein homeostasis. To investigate the role of these signaling pathways during inflam- matory conditions in the intestinal epithelium is one of our main interests. Previous work of our group has highlighted the relevance of both the activa- tion of endoplasmic reticulum UPR (ER UPR) and mitochondrial UPR (mtUPR) in IBD patients and in mouse models of intestinal inflammation [1,2]. To focus on the role of UPR in IECs during non-path- ologic and pathologic conditions we generated and investigate different UPR mouse models. The nATF6 mouse mimics a constitutive, epithelial- specific activation of the ATF6-mediated ER UPR branch. The ER UPR is initiated upon the accumulation of unfolded or misfolded proteins in the ER. This results in the recruitment of the chaperone Grp78 (Glucose regulated protein 78) from its binding partners to assist the folding of unfolded proteins. This triggers three branches of downstream signaling mediated by PERK (PKR-like ER kinase), ATF6 (Activating transcription factor 6), and IRE1 (Inositol requiring enzyme 1) to support refolding by translational attenuation, selective translation, and transcriptional regulation of ER UPR target genes [3]. As a response to the recruitment of Grp78 ATF6 is transported to the Golgi. There it is processed to the transcriptionally active form by the proteases S1P and S2P. This active transcription factor, which is overexpressed in the nATF6 mouse, activates, among others, the expression of molecular chap- erones such as Grp78 and Grp94 [4]. Besides its activation in IBD, ER UPR may be involv- ed in tumor formation since IBD patients have a higher risk of developing intestinal cancer [5] and ER UPR activation is also a common feature of can- cer cells. ASSOCIATED FELLOWS Page 70 | GRK Progress Report 2011-2014 Elena Lobner (M.Sc.) Nutrition and Immunology PhD Implications of ATF6 mediated activation of ER UPR in intestinal epithelial cells on intestinal homeostasis and tumorigenesis