Unfolded Protein Response Transducers Research Articles

The IRE1α/XBP1s Pathway Is Essential for the Glucose Response and Protection of β Cells.

Although glucose uniquely stimulates proinsulin biosynthesis in β cells, surprisingly little is known of the underlying mechanism(s). Here, we demonstrate that glucose activates the unfolded protein response transducer inositol-requiring enzyme 1 alpha (IRE1α) to initiate X-box-binding protein 1 (Xbp1) mRNA splicing in adult primary β cells. Using mRNA sequencing (mRNA-Seq), we show that unconventional Xbp1 mRNA splicing is required to increase and decrease the expression of several hundred mRNAs encoding functions that expand the protein secretory capacity for increased insulin production and protect from oxidative damage, respectively. At 2 wk after tamoxifen-mediated Ire1α deletion, mice develop hyperglycemia and hypoinsulinemia, due to defective β cell function that was exacerbated upon feeding and glucose stimulation. Although previous reports suggest IRE1α degrades insulin mRNAs, Ire1α deletion did not alter insulin mRNA expression either in the presence or absence of glucose stimulation. Instead, β cell failure upon Ire1α deletion was primarily due to reduced proinsulin mRNA translation primarily because of defective glucose-stimulated induction of a dozen genes required for the signal recognition particle (SRP), SRP receptors, the translocon, the signal peptidase complex, and over 100 other genes with many other intracellular functions. In contrast, Ire1α deletion in β cells increased the expression of over 300 mRNAs encoding functions that cause inflammation and oxidative stress, yet only a few of these accumulated during high glucose. Antioxidant treatment significantly reduced glucose intolerance and markers of inflammation and oxidative stress in mice with β cell-specific Ire1α deletion. The results demonstrate that glucose activates IRE1α-mediated Xbp1 splicing to expand the secretory capacity of the β cell for increased proinsulin synthesis and to limit oxidative stress that leads to β cell failure.

Comprehensive analysis of the endoplasmic reticulum stress response in the soybean genome: conserved and plant-specific features.

BackgroundDespite the relevance of the eukaryotic endoplasmic reticulum (ER)-stress response as an integrator of multiple stress signals into an adaptive response, knowledge about these ER-mediated cytoprotective pathways in soybean (Glycine max) is lacking. Here, we searched for genes involved in the highly conserved unfolded protein response (UPR) and ER stress-induced plant-specific cell death signaling pathways in the soybean genome.MethodsPreviously characterized Arabidopsis UPR genes were used as prototypes for the identification of the soybean orthologs and the in silico assembly of the UPR in soybean, using eggNOG v4.0 software. Functional studies were also conducted by analyzing the transcriptional activity of soybean UPR transducers.ResultsAs a result of this search, we have provided a complete profile of soybean UPR genes with significant predicted protein similarities to A. thaliana UPR-associated proteins. Both arms of the plant UPR were further examined functionally, and evidence is presented that the soybean counterparts are true orthologs of previously characterized UPR transducers in Arabidopsis. The bZIP17/bZI28 orthologs (GmbZIP37 and GmbZIP38) and ZIP60 ortholog (GmbZIP68) from soybean have similar structural organizations as their Arabidopsis counterparts, were induced by ER stress and activated an ERSE- and UPRE-containing BiP promoter. Furthermore, the transcript of the putative substrate of GmIREs, GmbZIP68, harbors a canonical site for IRE1 endonuclease activity and was efficiently spliced under ER stress conditions. In a reverse approach, we also examined the Arabidopsis genome for components of a previously characterized ER stress-induced cell death signaling response in soybean. With the exception of GmERD15, which apparently does not possess an Arabidopsis ortholog, the Arabidopsis genome harbors conserved GmNRP, GmNAC81, GmNAC30 and GmVPE sequences that share significant structural and sequence similarities with their soybean counterparts. These results suggest that the NRP/GmNAC81 + GmNAC30/VPE regulatory circuit may transduce cell death signals in plant species other than soybean.ConclusionsOur in silico analyses, along with current and previous functional data, permitted generation of a comprehensive overview of the ER stress response in soybean as a framework for functional prediction of ER stress signaling components and their possible connections with multiple stress responses.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1952-z) contains supplementary material, which is available to authorized users.

Differential activation of ER stress pathways in myelinating cerebellar tracts

Myelin production during brain development requires an increase in membrane protein and lipid production in oligodendrocytes and this primarily occurs in the endoplasmic reticulum (ER), an organelle which initiates the Unfolded Protein Response (UPR) when under stress. We hypothesise that the UPR is activated in white matter tracts during myelination in order to expand the ER capacity of oligodendrocytes.Using early and late stage markers, critical myelination time points were identified by immunohistochemistry in developing rat cerebellum. These were correlated to peaks in ER stress signalling by staining for activated UPR transducers (pIRE1, ATF6 and pPERK) and associated downstream molecules (peIF2α, PDI, GRP78, GRP94, CHOP and calreticulin) in cerebellar tracts III and IV. Gene expression in developing cerebellum was assessed by qPCR.Actively myelinating tracts were shown to have differential expression of pIRE1, PERK and ATF6 as well as UPR targets GRP94, GRP78 and PDI. Activated pIRE1-positive cells were widespread at P14 and P17 and at significantly higher numbers during myelination than at other stages. Nuclear-localised ATF6 (indicative of the active transcription factor) peaked at P10, concurrent with the initial phase of myelination. The percentage of cells positive for pPERK was less than 1% at postnatal ages but increased significantly in adult tissue. The downstream targets GRP78, GRP94 and PDI were significantly up-regulated at P17 compared to P7 and remained significantly elevated in adults. The majority of cells positive for these markers and ATF6 were oligodendrocytes as confirmed by dual-labelling. Although gene expression in the cerebellum for GRP78, GRP94 and PDI did not change significantly over time, ATF6 and XBP1s both showed significant fold changes between early and late timepoints.This data helps promote understanding of events occurring during developmental myelination and may have implications for the development of reparative treatments in diseases such as multiple sclerosis.

Ire1-mediated decay in mammalian cells relies on mRNA sequence, structure, and translational status.

Endoplasmic reticulum (ER) stress occurs when misfolded proteins overwhelm the capacity of the ER, resulting in activation of the unfolded protein response (UPR). Ire1, an ER transmembrane nuclease and conserved transducer of the UPR, cleaves the mRNA encoding the transcription factor Xbp1 at a dual stem-loop (SL) structure, leading to Xbp1 splicing and activation. Ire1 also cleaves other mRNAs localized to the ER membrane through regulated Ire1-dependent decay (RIDD). We find that during acute ER stress in mammalian cells, Xbp1-like SLs within the target mRNAs are necessary for RIDD. Furthermore, depletion of Perk, a UPR transducer that attenuates translation during ER stress, inhibits RIDD in a substrate-specific manner. Artificially blocking translation of the SL region of target mRNAs fully restores RIDD in cells depleted of Perk, suggesting that ribosomes disrupt SL formation and/or Ire1 binding. This coordination between Perk and Ire1 may serve to spatially and temporally regulate RIDD.

403 Tissue-Specific Induction of Activating Transcription Factor 6 Signaling Promotes Intestinal Dysbiosis and Colonic Tumorigenesis

The activating transcription factor 6 (ATF6) is one of the major transducers of the endoplasmic reticulum unfolded protein response (ER UPR). To study how ATF6 signaling affects intestinal epithelial cells (IEC) and intestinal health, nATF6IEC mice were investigated. These mice express the activated form of ATF6 (nATF6) specifically in IEC. The dissertation shows that nATF6 expression in IEC promotes tumorigenesis in the large intestine which is linked to dysbiosis of the intestinal microbiota. The nATF6IEC model and the analysis of ATF6 in colon cancer patients provide evidence for a contribution of ATF6 signaling to the pathogenesis of intestinal cancer.

Endoplasmic reticulum stress response and transcriptional reprogramming.

Endoplasmic reticulum stress response and transcriptional reprogramming.

Expression of citrate carrier gene is activated by ER stress effectors XBP1 and ATF6α, binding to an UPRE in its promoter

The Unfolded Protein Response (UPR) is an intracellular signaling pathway which is activated when unfolded or misfolded proteins accumulate in the Endoplasmic Reticulum (ER), a condition commonly referred to as ER stress. It has been shown that lipid biosynthesis is increased in ER-stressed cells. The Nε-lysine acetylation of ER-resident proteins, including chaperones and enzymes involved in the post-translational protein modification and folding, occurs upon UPR activation. In both ER proteins acetylation and lipid synthesis, acetyl-CoA is the donor of acetyl group and it is transported from the cytosol into the ER. The cytosolic pool of acetyl-CoA is mainly derived from the activity of mitochondrial citrate carrier (CiC). Here, we have demonstrated that expression of CiC is activated in human HepG2 and rat BRL-3A cells during tunicamycin-induced ER stress. This occurs through the involvement of an ER stress responsive region identified within the human and rat CiC proximal promoter. A functional Unfolded Protein Response Element (UPRE) confers responsiveness to the promoter activation by UPR transducers ATF6α and XBP1. Overall, our data demonstrate that CiC expression is activated during ER stress through the binding of ATF6α and XBP1 to an UPRE element located in the proximal promoter of Cic gene. The role of ER stress-mediated induction of CiC expression has been discussed.

Fine tuning of the UPR by the ubiquitin ligases Siah1/2.

The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). Yet, it is not known how UPR-signaling coordinates adaptation versus cell death. Previous studies suggested that signaling through PERK/ATF4 is required for cell death. We show that high levels of ER stress (i.e., ischemia-like conditions) induce transcription of the ubiquitin ligases Siah1/2 through the UPR transducers PERK/ATF4 and IRE1/sXBP1. In turn, Siah1/2 attenuates proline hydroxylation of ATF4, resulting in its stabilization, thereby augmenting ER stress output. Conversely, ATF4 activation is reduced upon Siah1/2 KD in cultured cells, which attenuates ER stress-induced cell death. Notably, Siah1a+/−::Siah2−/− mice subjected to neuronal ischemia exhibited smaller infarct volume and were protected from ischemia-induced death, compared with the wild type (WT) mice. In all, Siah1/2 constitutes an obligatory fine-tuning mechanism that predisposes cells to death under severe ER stress conditions.

Rifampicin Protects PC12 Cells from Rotenone-Induced Cytotoxicity by Activating GRP78 via PERK-eIF2α-ATF4 Pathway

Rifampicin has been proposed as a therapeutic candidate for Parkinson's disease (PD). We previously showed that rifampicin was neuroprotective in PD models in vivo and in vitro. However, the molecular mechanisms underlying are not fully elucidated. In this study, using the comprehensive proteomic analysis, we identified that the 78 kDa glucose-regulated protein (GRP78), a hallmark of the unfolded protein response (UPR), was upregulated in rifampicin-treated PC12 cells. Western blot analysis confirmed GRP78 activation. GRP78 functions cytoprotectively in stressed cells, therefore, we hypothesized that GRP78 mediated rifampicin-induced neuroprotection. Using RNA interference, we found that GRP78 gene knockdown significantly attenuated the neuroprotective effects of rifampicin. Next, we examined three UPR transducers, namely, protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol requiring kinase α (IREα) and activating transcription factor 6 (ATF 6), and how they regulated rifampicin-stimulated GRP78 expression. Our results showed that PERK, eukaryotic initiation factor 2α (eIF2α), and activating transcription factor 4 (ATF4) were activated in rifampicin-treated PC12 cells. Silencing the ATF4 gene using RNAi inhibited GRP78 stimulation. Interestingly, we did not detect significant IREα activation, X-box binding protein 1 mRNA splicing, or ATF6 cleavage up to 24 h after rifampicin treatment. Taken together, our data suggested that rifampicin induced GRP78 via the PERK-eIF2α-ATF4 pathway to protect neurons against rotenone-induced cell damage. Targeting molecules in this pathway could be a novel therapeutic approach for PD treatment.

P-226 Innate Immune Sensing of Gut Microbes by the Endoplasmic Reticulum (ER) Protein IRE1 of Barrier Intestinal Epithelial Cells

The plasma membrane and all membrane-bound organelles except for the Golgi and endoplasmic reticulum (ER) are equipped with pattern-recognition molecules to sense microbes or their products and induce innate immunity for host defense. We used polarized human epithelial cells to examine the cytokines production by qRT-PCR. Also using various cell lines including IRE1a, IRE1b, RIG-I, MAVS knockdown cell lines or knockout MEF, we examined the signalling pathway. We recently reported that Inositol-REquiring-1α (IRE1α), an ER protein that signals in the unfolded protein response (UPR), is activated to induce inflammation by cholera and Shiga toxins as they co-opt the ER to cause disease (Cell Host Microbe 2013). Other known UPR transducers, including the IRE1α effector XBP1 are dispensable for this signaling. The inflammatory response depends instead on the RNase activity of IRE1α and retinoic-acid inducible gene 1 (RIG-I), a cytosolic sensor of RNA fragments. These observations implicate Regulated IRE1α-Dependent Decay of mRNA (RIDD) in a novel innate immune mechanism of host defense originating from within the ER lumen. Because a second isoform of IRE1α (IRE1b) is expressed almost exclusively in intestinal epithelial cells and whose absence predisposes to colitis, we hypothesize that the IRE1-RIDD pathway may act as a generalized mechanism of innate immune surveillance in the human intestine to affect the composition of the microbiome and regulate intestinal mucosal immunity. Here, we report initial studies testing whether IRE1b acts in innate immunity and extend our investigations to in vivo mouse models lacking the mitochondrial scaffolding protein MAVS, which is predicted to be critical for signal transduction in the IRE1-RIDD pathway.

The Unfolded Protein Response Transducer ATF6 Represents a Novel Transmembrane-type Endoplasmic Reticulum-associated Degradation Substrate Requiring Both Mannose Trimming and SEL1L Protein

Proteins misfolded in the endoplasmic reticulum (ER) are cleared by the ubiquitin-dependent proteasome system in the cytosol, a series of events collectively termed ER-associated degradation (ERAD). It was previously shown that SEL1L, a partner protein of the E3 ubiquitin ligase HRD1, is required for degradation of misfolded luminal proteins (ERAD-Ls substrates) but not misfolded transmembrane proteins (ERAD-Lm substrates) in both mammalian and chicken DT40 cells. Here, we analyzed ATF6, a type II transmembrane glycoprotein that serves as a sensor/transducer of the unfolded protein response, as a potential ERAD-Lm substrate in DT40 cells. Unexpectedly, degradation of endogenous ATF6 and exogenously expressed chicken and human ATF6 by the proteasome required SEL1L. Deletion analysis revealed that the luminal region of ATF6 is a determinant for SEL1L-dependent degradation. Chimeric analysis showed that the luminal region of ATF6 confers SEL1L dependence on type I transmembrane protein as well. In contrast, degradation of other known type I ERAD-Lm substrates (BACE457, T-cell receptor-α, CD3-δ, and CD147) did not require SEL1L. Thus, ATF6 represents a novel type of ERAD-Lm substrate requiring SEL1L for degradation despite its transmembrane nature. In addition, endogenous ATF6 was markedly stabilized in wild-type cells treated with kifunensine, an inhibitor of α1,2-mannosidase in the ER, indicating that degradation of ATF6 requires proper mannose trimming. Our further analyses revealed that the five ERAD-Lm substrates examined are classified into three subgroups based on their dependence on mannose trimming and SEL1L. Thus, ERAD-Lm substrates are degraded through much more diversified mechanisms in higher eukaryotes than previously thought.

Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis

In rheumatoid arthritis (RA), macrophage is one of the major sources of inflammatory mediators. Macrophages produce inflammatory cytokines through toll-like receptor (TLR)-mediated signalling during RA. Herein, we studied macrophages from the synovial fluid of RA patients and observed a significant increase in activation of inositol-requiring enzyme 1α (IRE1α), a primary unfolded protein response (UPR) transducer. Myeloid-specific deletion of the IRE1α gene protected mice from inflammatory arthritis, and treatment with the IRE1α-specific inhibitor 4U8C attenuated joint inflammation in mice. IRE1α was required for optimal production of pro-inflammatory cytokines as evidenced by impaired TLR-induced cytokine production in IRE1α-null macrophages and neutrophils. Further analyses demonstrated that tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6) plays a key role in TLR-mediated IRE1α activation by catalysing IRE1α ubiquitination and blocking the recruitment of protein phosphatase 2A (PP2A), a phosphatase that inhibits IRE1α phosphorylation. In summary, we discovered a novel regulatory axis through TRAF6-mediated IRE1α ubiquitination in regulating TLR-induced IRE1α activation in pro-inflammatory cytokine production, and demonstrated that IRE1α is a potential therapeutic target for inflammatory arthritis.

The unfolded protein response element IRE1α senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling.

The plasma membrane and all membrane-bound organelles except for the Golgi and endoplasmic reticulum (ER) are equipped with pattern-recognition molecules to sense microbes or their products and induce innate immunity for host defense. Here, we report that inositol-requiring-1α (IRE1α), an ER protein that signals in the unfolded protein response (UPR), is activated to induce inflammation by binding a portion of cholera toxin as it co-opts the ER to cause disease. Other known UPR transducers, including the IRE1α-dependent transcription factor XBP1, are dispensable for this signaling. The inflammatory response depends instead on the RNase activity of IRE1α to degrade endogenous mRNA, a process termed regulated IRE1α-dependent decay (RIDD) of mRNA. The mRNA fragments produced engage retinoic-acid inducible gene 1 (RIG-I), a cytosolic sensor of RNA viruses, to activate NF-κB and interferon pathways. We propose IRE1α provides for a generalized mechanism of innate immune surveillance originating within the ER lumen.

Innate immune sensing of a bacterial protein in the ER by IRE1α

The plasma membrane and all membrane‐bound organelles except for the Golgi and endoplasmic reticulum (ER) are equipped with pattern‐recognition molecules to sense microbes or their products and induce innate immunity for host defense. Here, we report that Inositol‐REquiring‐1α (IRE1α), an ER protein that signals in the unfolded protein response (UPR), is activated to induce inflammation by cholera and Shiga toxins as they co‐opt the ER to cause disease. Other known UPR transducers, including the IRE1α effector XBP1 are dispensable for this signaling. The inflammatory response depends instead on the RNase activity of IRE1α and retinoic‐acid inducible gene 1 (RIG‐I), a cytosolic sensor of RNA fragments. These observations implicate Regulated IRE1α‐Dependent Decay of mRNA (RIDD) in a novel innate immune mechanism of host defense originating from within the ER lumen.Grant Funding Source: NIH R01/CCFA

MicroRNA-199a-5p protects hepatocytes from bile acid-induced sustained endoplasmic reticulum stress

Sustained endoplasmic reticulum (ER) stress has been linked to cell death and the pathogenesis of many liver diseases, including toxic liver, cholestasis, and infectious liver disease. The cellular pathways that attenuate hepatic ER stress have been the focus of many recent studies, but the role of microRNAs (miRNA) in this process remains unknown. Here, we report that one of the most abundant miRNAs in hepatocytes, miR-199a-5p, was elevated in both bile acid- and thapsigargin (TG)-stimulated cultured hepatocytes, as well as in the liver of bile duct-ligated mice. We identify the misfolded protein chaperone GRP78, as well as the unfolded protein response transducers endoplasmic reticulum to nucleus signaling 1 and activating transcription factor 6 as direct targets of miR-199a-5p, and show that endogenous miR-199a-5p represses the 3′ untranslated regions (UTRs) of their mRNAs. Through gain-of-function and loss of function approaches, we demonstrate that the elevated miR-199-5p disrupts sustained ER stress and prevents hepatocytes from undergoing bile acid- or TG-induced cell death. Furthermore, we reveal that the transcription factor AP-1 is a strong positive regulator of miR-199a-5p. In brief, our study demonstrates that AP-1/miR-199a-5p and ER stress mediators form a feedback loop, which shields hepatocytes from sustained ER stress and protects the liver from injury. On the basis of these findings, we also suggest that the miRNA miR-199a-5p is a potential target for clinical approaches aiming to protect hepatocytes in liver disease.

Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains.

Endoplasmic reticulum (ER) stress sensors use a related luminal domain to monitor the unfolded protein load and convey the signal to downstream effectors, signaling an unfolded protein response (UPR) that maintains compartment-specific protein folding homeostasis. Surprisingly, perturbation of cellular lipid composition also activates the UPR, with important consequences in obesity and diabetes. However, it is unclear if direct sensing of the lipid perturbation contributes to UPR activation. We found that mutant mammalian ER stress sensors, IRE1α and PERK, lacking their luminal unfolded protein stress-sensing domain, nonetheless retained responsiveness to increased lipid saturation. Lipid saturation-mediated activation in cells required an ER-spanning transmembrane domain and was positively regulated in vitro by acyl-chain saturation in reconstituted liposomes. These observations suggest that direct sensing of the lipid composition of the ER membrane contributes to the UPR.

Unfolded protein response activates glycogen synthase kinase-3 via selective lysosomal degradation

The unfolded protein response (UPR) is a stress response that is activated upon disturbed homeostasis in the endoplasmic reticulum. In Alzheimer's disease, as well as in other tauopathies, the UPR is activated in neurons that contain early tau pathology. A recent genome-wide association study identified genetic variation in a UPR transducer as a risk factor for tauopathy, supporting a functional connection between UPR activation and tau pathology. Here we show that UPR activation increases the activity of the major tau kinase glycogen synthase kinase (GSK)-3 in vitro via a selective removal of inactive GSK-3 phosphorylated at Ser21/9. We demonstrate that this is mediated by the autophagy/lysosomal pathway. In brain tissue from patients with different tauopathies, lysosomal accumulations of pSer21/9 GSK-3 are found in neurons with markers for UPR activation. Our data indicate that UPR activation increases the activity of GSK-3 by a novel mechanism, the lysosomal degradation of the inactive pSer21/9 GSK-3. This may provide a functional explanation for the close association between UPR activation and early tau pathology in neurodegenerative diseases.

RETRACTED: Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-β1 secretion

Mutations in the genes encoding the lung surfactant proteins are found in patients with interstitial lung disease and lung cancer, but their pathologic mechanism is poorly understood. Here we show that bronchoalveolar lavage fluid from humans heterozygous for a missense mutation in the gene encoding surfactant protein (SP)-A2 (SFTPA2) contains more TGF-β1 than control samples. Expression of mutant SP-A2 in lung epithelial cells leads to secretion of latent TGF-β1, which is capable of autocrine and paracrine signaling. TGF-β1 secretion is not observed in lung epithelial cells expressing the common SP-A2 variants or other misfolded proteins capable of increasing cellular endoplasmic reticulum stress. Activation of the unfolded protein response is necessary for maximal TGF-β1 secretion because gene silencing of the unfolded protein response transducers leads to an ∼50% decrease in mutant SP-A2-mediated TGF-β1 secretion. Expression of the mutant SP-A2 proteins leads to the coordinated increase in gene expression of TGF-β1 and two TGF-β1-binding proteins, LTBP-1 and LTBP-4; expression of the latter is necessary for secretion of this cytokine. Inhibition of the TGF-β autocrine positive feedback loop by a pan-TGF-β-neutralizing antibody, a TGF-β receptor antagonist, or LTBP gene silencing results in the reversal of TGF-β-mediated epithelial-to-mesenchymal transition and cell death. Because secretion of latent TGF-β1 is induced specifically by mutant SP-A2 proteins, therapeutics targeted to block this pathway may be especially beneficial for this molecularly defined subgroup of patients.

Plant transducers of the endoplasmic reticulum unfolded protein response

The unfolded protein response (UPR) activates a set of genes to overcome accumulation of unfolded proteins in the endoplasmic reticulum (ER), a condition termed ER stress, and constitutes an essential part of ER protein quality control that ensures efficient maturation of secretory and membrane proteins in eukaryotes. Recent studies on Arabidopsis and rice identified the signaling pathway in which the ER membrane-localized ribonuclease IRE1 (inositol-requiring enzyme 1) catalyzes unconventional cytoplasmic splicing of mRNA, thereby producing the active transcription factor Arabidopsis bZIP60 (basic leucine zipper 60) and its ortholog in rice. Here we review recent findings identifying the molecular components of the plant UPR, including IRE1/bZIP60 and the membrane-bound transcription factors bZIP17 and bZIP28, and implicating its importance in several physiological phenomena such as pathogen response.

Stress management: How the unfolded protein response impacts fatty liver disease

Induction of the unfolded protein response (UPR) is recognized as central to fatty liver disease (FLD) pathophysiology. This pathway may be a potential therapeutic target for FLD, as well as other diseases. However, fundamental questions as to how UPR contributes to FLD remain unanswered. Conflicting data suggest that this pathway can both protect against and augment this disease. Here, we review the relationship between protein secretion, endoplasmic reticulum function (ER), and UPR activation. The UPR serves to maintain secretory pathway homeostasis by enhancing the protein folding environment in the ER, and we review data investigating the role for individual UPR players in fatty liver (steatosis). We explore a novel concept in the field that all cases of UPR activation do not equal "ER stress". Rather, different types of UPRs that can either protect against or cause FLD are discussed. Refining our current understanding of this complex pathway is particularly important, as drugs that affect the protein folding environment in the ER and affect UPR activation are being successful in clinical trials for FLD.