Stimulation of an Unfolded Protein Response Impairs MHC Class I Expression

Almeida, Sérgio Fernandes de; Fleming, John; Azevedo, Jorge E.; Carmo‐Fonseca, Maria; Sousa, Maria de

doi:10.4049/jimmunol.178.6.3612

Cited by 72 publications

(83 citation statements)

References 44 publications

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“…38,39 The common human HFE C282Y (murine C294Y) disease-causing mutation alters the secondary structure of HFE, rendering it unable to reach the cell surface, 10 and induces UPR and ER stress in cell culture systems. 40 To test the hypothesis that it might have a similar effect in vivo, we created TTR-Hfe C294Y transgenic animals (Hfe C294Y , Figure 3A) and analyzed parameters of iron metabolism. We bred Hfe C294Y transgenic animals to Hfe Ϫ/Ϫ mice of the same genetic background, and compared Hfe Ϫ/Ϫ mice carrying the Hfe C294Y transgene to Hfe Ϫ/Ϫ littermates.…”

Section: Overexpression Of Hfe or Hfe Mutant Proteins Does Not Initiamentioning

confidence: 99%

“…Alternatively, it has been shown that basic amino acids immediately after the transmembrane domain of membrane proteins are necessary for proper insertion and topology. 32 Thus, it is possible that loss of these amino acids in the Hfe ⌬CD truncated protein leads to improper or decreased membrane insertion causing a diminution in protein activity at the cell membrane.Overexpression of mutant HFE in cell culture triggers an unfolded protein response (UPR) 40 and ER stress can induce hepcidin production. 38,39 Using 2 separate methods we were unable to detect ER stress in any of the HFE overexpressing animals, including animals overexpressing an ortholog of the common C282Y human missense mutation that has been shown to induce ER stress in cell culture.…”

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confidence: 99%

“…38,39 Using 2 separate methods we were unable to detect ER stress in any of the HFE overexpressing animals, including animals overexpressing an ortholog of the common C282Y human missense mutation that has been shown to induce ER stress in cell culture. 40 It is possible that there is acute stress early in the development of the mice, but that cellular adaptations to chronic overexpression of proteins occur over time.HJV is crucial for hepcidin production and hepcidin mRNA is nearly absent when HJV is absent. 7,25,26 It is not yet clear, however, whether other known hepcidin regulators, including HFE and TFR2, act in concert with, or independently of HJV.…”

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Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Schmidt

Andrews

Fleming

2010

Blood

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Mutations in HFE cause the most common form of hereditary hemochromatosis (HH). We previously showed that liverspecific, transgenic overexpression of murine Hfe stimulates production of the iron regulatory hormone hepcidin. Here, we developed several additional transgenic mouse strains to further interrogate the structural basis of HFE function in the pathophysiology of HH. We hypothesized that the small, cytoplasmic domain of HFE might be necessary for HFE-mediated induction of hepcidin. We demonstrate that, like the full-length protein, overexpression of Hfe proteins lacking the cytoplasmic domain leads to hepcidin induction, iron deficiency and a hypochromic, microcytic anemia. However, high-level expression of a liver-specific Hfe transgene carrying the mouse equivalent of the common HFE C282Y human diseasecausing mutation (murine C294Y ) IntroductionThe common iron overload disease hereditary hemochromatosis (HH) is caused by a chronic increase in dietary iron absorption. A unifying model has emerged to explain the pathogenesis of genetically distinct forms of HH. 1 Aberrant iron homeostasis results from interruption of a regulatory axis involving the hormone hepcidin, predominantly produced by hepatocytes, and the iron exporter ferroportin, present in duodenal enterocytes and macrophages. Hepcidin binds to ferroportin to trigger its internalization and lysosomal degradation. 2 In this way, circulating hepcidin controls both intestinal iron absorption and the release of iron from macrophages into the plasma. There are 3 general classes of genetic defects known to cause HH. First, recessive mutations in the gene encoding hepcidin (HAMP) prevent the production of functional peptide. 3 Second, some dominant mutations in ferroportin (encoded by SLC40A1) render it resistant to hepcidin regulation. 4,5 Third, recessive mutations in the genes encoding HFE, transferrin receptor-2 (TFR2) or hemojuvelin (HFE2 or HJV), alter hepcidin expression by the hepatocyte. [6][7][8] Most hemochromatosis patients are homozygous for a C282Y mutation in HFE (equivalent to C294Y in mouse Hfe), an atypical major histocompatibility complex (MHC) class I-like molecule 9 that heterodimerizes with ␤2-microglobulin 10 and associates with the major transferrin receptor (TFR1). 11,12 HFE is similar to MHC class I proteins in that it contains a signal sequence, 3 sequential immunoglobulin superfamily ␣-domains, and a transmembrane domain followed by a 19 amino acid, cytoplasmic domain. The cytoplasmic domain of human HFE has 2 conserved, potential phosphorylation sites at 335 Ser and 342 Tyr. Although it has been shown that the cytoplasmic domains of Class I MHC proteins are not necessary for transmitting T-cell activation signals, 13 and overexpression of HFE proteins containing either a S335M or Y342C mutation decreased ferritin levels in HEK293 cells, 14 we hypothesized that these 2 phosphorylation sites might be involved in HFE-mediated hepcidin induction in vivo. Cytoplasmic motifs similar to the YVLA ( 342 Tyr) motif in HFE function ...

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Section: Overexpression Of Hfe or Hfe Mutant Proteins Does Not Initiamentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Schmidt

Andrews

Fleming

2010

Blood

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“…In other tissues, mutations in genes encoding secretory pathway proteins have been found to cause endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response (UPR), a set of evolutionarily conserved signaling pathways activated upon ER stress (22)(23)(24)(25)(26)(27)(28). UPR has been implicated in the pathogenesis of many conformational diseases, such as Alzheimer disease, Parkinson disease, and diabetes, and is being investigated in many others (29 -33).…”

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Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract

Firtina

Danysh

Bai

et al. 2009

Journal of Biological Chemistry

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Human diseases caused by mutations in extracellular matrix genes are often associated with an increased risk of cataract and lens capsular rupture. However, the underlying mechanisms of cataract pathogenesis in these conditions are still unknown. Using two different mouse models, we show that the accumulation of collagen chains in the secretory pathway activates the stress signaling pathway termed unfolded protein response (UPR). Transgenic mice expressing ectopic Col4a3 and Col4a4 genes in the lens exhibited activation of IRE1, ATF6, and PERK associated with expansion of the endoplasmic reticulum and attenuation of general protein translation. The expression of the transgenes had adverse effects on lens fiber cell differentiation and eventually induced cell death in a group of transgenic fiber cells. In Col4a1 ؉/⌬ex40 mutant mice, the accumulation of mutant chains also caused low levels of UPR activation. However, cell death was not induced in mutant lenses, suggesting that low levels of UPR activation are not proapoptotic. Collectively, the results provide in vivo evidence for a role of UPR in cataract formation in response to accumulation of terminally unfolded proteins in the endoplasmic reticulum.The ocular lens is a transparent, cellular structure that refracts light onto the retina, resulting in high resolution vision. Many environmental risk factors and single gene defects are known or hypothesized to result in clouding of the lens, a condition known as cataract. Cataract is the primary cause of blindness worldwide (1, 2), with autosomal dominant congenital cataract being the leading cause of treatable childhood blindness (3, 4). Cataract surgery is the most commonly performed surgical operation in the United States and consumes 60% of the Medicare budget for vision (5, 6).Cataract can be a multifactorial disease and is often associated with systemic or genetic disorders, such as diabetes and Lowe syndrome (7-9). Notably, human diseases caused by mutations in extracellular matrix (ECM) 4 genes are also often associated with an increased risk of cataract. Stickler and Marshall syndromes are two disorders caused by mutations in the COL2A1 gene that are associated with the early onset of distinctive cataracts (10, 11). Alport syndrome, caused by mutations in either the COL4A3, COL4A4, or COL4A5 genes, is also associated with lens capsule abnormalities and cataract formation (12)(13)(14). Humans carrying mutations in the COL4A1 locus often exhibit lens abnormalities and cataracts along with porencephaly and sporadic intracerebral hemorrhage (15-19). To date, approximately 13 independent mutations in the mouse Col4a1 locus and three independent mutations in mouse Col4a2 locus have been found to cause vacuolar cataract and lens abnormalities in mice (19 -21). However, the underlying mechanisms of cataract pathogenesis resulting from these collagen mutations are still unknown.In other tissues, mutations in genes encoding secretory pathway proteins have been found to cause endoplasmic reticulum (ER) stress and...

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“…2016. 46: 929-940 reported in the overexpression model of a mutant HFE protein, which does not fold properly in the ER [36]. In this study, we set up a biochemical assay combined RP-HPLC fractionation with T-cell hybridoma response, which allowed us to quantify the produced amount of the OVA peptide in the cells exposed to hypoxia alone, glucose-deprivation alone, or both hypoxia and glucose deprivation.…”

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Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8⁺ T‐cell recognition of stressed cells

et al. 2016

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Hypoxia and glucose deprivation are often observed in the microenvironment surrounding solid tumors in vivo. However, how they interfere with MHC class I antigen processing and CD8 + T-cell responses remains unclear. In this study, we analyzed the production of antigenic peptides presented by classical MHC class I in mice, and showed that it is quantitatively decreased in the cells exposed to either hypoxia or glucose deprivation. In addition, we unexpectedly found increased surface expression of HLA-E in human and Qa-1 in mouse tumor cells exposed to combined oxygen and glucose deprivation. The induced Qa-1 on the stressed tumor model interacted with an inhibitory NKG2/CD94 receptor on activated CD8 + T cells and attenuated their specific response to the antigen. Our results thus suggest that microenvironmental stresses modulate not only classical but also nonclassical MHC class I presentation, and confer the stressed cells the capability to escape from the CD8 + T-cell recognition.Keywords: Antigen presentation r Glucose deprivation hypoxia r HLA-E r MHC class I r Microenvironmental stress r Qa-1 Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSolid tumors provide a special microenvironment that alters the biological aspects of the cells within [1]. Because of aberrant Correspondence: Dr. Takayuki Kanaseki e-mail: kanaseki@sapmed.ac.jp and disorganized vasculature, tumor cells inside a mass are often exposed to chronic hypoxia, which induces stress-related gene expression as well as resistance to apoptosis, radiation, and chemotherapy [2,3]. Moreover, tumor cells predominantly use the tricarboxylic acid cycle rather than oxidative phosphorylation for energy production (Warburg effect) and they are exposed to severe glucose deprivation [4,5]. The biological adaptation models of tumor cells to survive under such combined-stress condition C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 930Takanori Sasaki et al. Eur. J. Immunol. 2016. 46: 929-940 have been established [6][7][8][9], however the understanding of how the microenvironmental stresses interfere MHC class I antigen processing and CD8 + T-cell responses is incomplete. MHC class I molecules are expressed on most nucleated cells and determine the outcome of CD8 + T-cell mediated immune surveillance. They are classified into highly polymorphic classical MHC class I molecules and nonpolymorphic nonclassical MHC class I molecules. The classical MHC I molecules on the surface present short peptides originating from endogenous self or foreign proteins and form complexes with a diverse set of peptide (pMHC I) [10,11]. Such short peptides are generally 8-10-mer in length and conserve anchor residues that locate at discrete positions, allowing the peptide to be bound to MHC I molecules [12]. The peptides are produced by MHC I antigen processing that begins in the cytosol and continues in the ER where the precursor peptides are optimized for binding and finally load...

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Stimulation of an Unfolded Protein Response Impairs MHC Class I Expression

Cited by 72 publications

References 44 publications

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract

Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8⁺ T‐cell recognition of stressed cells

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Stimulation of an Unfolded Protein Response Impairs MHC Class I Expression

Cited by 72 publications

References 44 publications

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Hepcidin induction by transgenic overexpression of Hfe does not require the Hfe cytoplasmic tail, but does require hemojuvelin

Abnormal Expression of Collagen IV in Lens Activates Unfolded Protein Response Resulting in Cataract

Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8+ T‐cell recognition of stressed cells

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Microenvironmental stresses induce HLA‐E/Qa‐1 surface expression and thereby reduce CD8⁺ T‐cell recognition of stressed cells