Accumulation of non- or misfolded proteins in the ER triggers an adaptive response, the unfolded protein response (UPR) that attenuates protein de novo synthesis and enhances the production of chaperones that facilitate protein folding [21] Additionally, enhanced proteosomal degradation of misfolded proteins (proteotoxicity) and apoptosis is induced after a cascade of molecular reactions. There are three distinct pathways triggered by ER stress, all of which induce find more the expression of different genes aiming to

restore the normal function of the ER, and in case it fails, apoptosis will be induced (Rutkowski & Kaufmann, 2004). The pathways are based on activation of the chaperone BiP (or also called GRP78) that dissociates from transmembrane proteins (ER-resident signaling proteins), such as protein kinase like ER kinase

(PERK), inositol-requiring protein 1 (IRE1) and activating transcription factor 6 (ATF6). PERK then phosphorylates eukaryotic elongation factor 2α (eIF2α), which leads to a general translation block, but also to a specific buy Panobinostat translation of ATF4 [20]. IRE1 turns X-box binding protein 1 (XBP-1) mRNA into the transcription factor XBP-1s. ATF6 gets phosphorylated and turns into a transcription factor. XBP-1s and ATF6 positively lead to up-regulation of a wide variety of ER stress target genes, including chaperones BiP (GRP78). ATF4 and ATF6 result in up-regulation of CCAAT/enhancer-binding protein-homologous protein CHOP (or also called GADD153), which is a pro-apoptotic marker gene. Overexpression of CHOP promotes cell death. On this basis, the ER stress response can be assessed by selective markers such as induction of the chaperone BiP, splicing of XBP-1 mRNA, and phosphorylation of eIF2α⋅ The ER stress response and associated UPR has important consequences, including apoptosis. It accompanies acute and chronic liver diseases and plays a significant role in liver pathogenesis [13]. Additionally ER stress can activate NFκB [30] leading to the expression of interferons (INFs) Type I and inflammatory cytokines like TNF-α [1]. Interferons have a wide variety of biological activities including antiviral,

immunomodulatory, antiangiogenic and antiproliferative and promote apoptosis [42]. Tryptophan synthase IFNs stimulate the expression of anti-viral genes (ISG) [1] and induce several hundred of genes [14]. Most prominent is ISG-15, a broadly active non-specific antiviral effector and an ubiquitin-like protein that conjugates to over 150 cellular target proteins [35]. TNF-α is involved in the inflammatory response, apoptosis, cell proliferation and cell differentiation. Inflammatory and immune responses are regulated by multiple signaling pathways. Among them are the NFκB and mitogen-activated protein kinase (MAPK) signaling pathways, which include many proteins including MAPK (originally called the extracellular signal-regulated kinase1/2 ERK1/2), p38, CREB, cMyc and c-Jun N-terminal kinase (JNK) pathways.