The endoplasmic reticulum stress response in immunity and autoimmunity

Abstract

Many exogenous sources of stress can lead to cell death. In recent years, endogenous cellular sources of stress have also been identified, including the stress that arises from the accumulation of unfolded proteins within a cell's endoplasmic reticulum (ER). To counterbalance this type of ER stress, higher eukaryotic cells possess a three-pronged signal-transduction pathway termed the unfolded-protein response (UPR). This Review focuses on the role of the UPR in the mammalian immune system and how manipulation of this complex signalling pathway may be of therapeutic benefit in human disease.

Enhanced Biosynthesis of Coagulation Factor VIII through Diminished Engagement of the Unfolded Protein Response

“…Therefore, UPR was induced in BHKs expressing recombinant fVIII using the potent UPR inducer, thapsigargin, and a dose responsive decrease in fVIII expression was observed (data not shown). In XBP1s has been shown to inhibit UPR induced translational arrest and cause up-regula- tion of glycosylation and disulfide bond formation (19). Constitutive expression of XBP1s was found to be beneficial for the expression of both rhfVIII and rpfVIII (Fig.…”

Consensus guidelines for the detection of immunogenic cell death

“…Several assays are currently available for the detection of the different arms of the ER stress response. 136,[254][255][256] For instance, the phosphorylation state of EIF2A and/or of the major EIF2A kinases, including EIF2A kinase 1 (EIF2AK1, best known as HRI), 257 EIF2AK2 (best known as PKR), 258 and EIF2AK3 (best known as PERK), [259][260][261] can be assessed by immunoblotting, flow cytometry or immunofluorescence microscopy with phosphoneoepitope-specific antibodies. 260 The splicing status of X-box binding protein 1 (XBP1) mRNA, reflecting the activation of the ER stress sensor endoplasmic reticulum to nucleus signaling 1 (ERN1, best known as IRE1a), can be monitored by quantitative real-time RT-PCR, 262 as well as by flow cytometry or fluorescence microscopy, either in cells that express a fluorescently-tagged version of XBP1 263 or upon the administration of a self-quenched RNA probe that can be cleaved by IRE1a.…”

ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

“…The unfolded protein response (UPR) is a cytoprotective response to ER stress that arises when misfolded proteins accumulate in this organelle (Schröder and Kaufman, 2005;Todd et al, 2008;Walter and Ron, 2011). In metazoans, three core UPR-associated pathways coordinate an adaptive response to ER stress that results in expansion of the ER, promotion of ER-associated degradation and chaperone functions and, when unabated, cellular death by apoptosis.…”

“…In metazoans, three core UPR-associated pathways coordinate an adaptive response to ER stress that results in expansion of the ER, promotion of ER-associated degradation and chaperone functions and, when unabated, cellular death by apoptosis. The evolutionarily most conserved UPR branch consists of inositol-requiring enzyme 1 (Ire1; encoded by Ern1), an ER stress sensor, and the transcription factor X-box-binding protein 1 (Xbp1) as its effector (Schröder and Kaufman, 2005;Ron and Walter, 2007;Todd et al, 2008;Kohno, 2010;Walter and Ron, 2011). Ire1 activates Xbp1 by conversion of unspliced Xbp1 (Xbp1u) +/+(IEC) and Xbp1 /(IEC) mice for transcripts representative of the ISC signature (J; Muñoz et al, 2012) or Paneth cell signature (K; Sato et al, 2011) by RT-pPCR (n = 12/11; Student's t test).…”