Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Bitzer, Annegret; Basler, Michael; Groettrup, Marcus

doi:10.1016/j.molimm.2015.11.004

Cited by 11 publications

(7 citation statements)

References 37 publications

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“…Indeed, IL-2Rα is mistargeted to the cytosol due to a lack of SRP engagement, resulting in the rapid degradation of nascent proteins and thus serving as an opportunity to provide an epitope peptide efficiently 47 . Although there might be redundant pathway(s) for the role of BAG6 in antigen presentation 59 , our results support the hypothesis that BAG6 might act as a critical factor for the proteasome-mediated degradation of a mislocalized TMD protein that possesses a non-cleaved SS (with a T7-tag) at its N-terminus. It might be interesting to note that HLA is one the most polymorphic self-gene products encoded in the human genome.…”

Section: Discussionsupporting

confidence: 83%

Elimination of a signal sequence-uncleaved form of defective HLA protein through BAG6

Yamamoto

Hayashishita

Minami

et al. 2017

Sci Rep

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A portion of newly synthesized transmembrane domain proteins tend to fail to assemble correctly in the lumen of the endoplasmic reticulum, thus resulting in the production of a signal sequence-uncleaved form of the defective species. Although the efficient degradation of these mistargeted polypeptides is crucial, the molecular mechanism of their elimination pathway has not been adequately characterized. In this study, we focused on one such cryptic portion of a defective transmembrane domain protein, HLA-A, and show that a part of HLA-A is produced as a signal sequence-uncleaved labile species that is immediately targeted to the degradation pathway. We found that both BAG6 and proteasomes are indispensable for elimination of mislocalized HLA-A species. Furthermore, defective HLA-A is subjected to BAG6-dependent solubilization in the cytoplasm. These observations suggest that BAG6 acts as a critical factor for proteasome-mediated degradation of mislocalized HLA-A with a non-cleaved signal sequence at its N-terminus.

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Section: Discussionsupporting

confidence: 83%

Elimination of a signal sequence-uncleaved form of defective HLA protein through BAG6

Yamamoto

Hayashishita

Minami

et al. 2017

Sci Rep

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“…To clarify the impact of selected reference genes on relative expression analysis, we analyzed the transcript level of BAG gene, which is conserved and ubiquitously expressed in higher eukaryotes (Bitzer et al, 2016). BAG , as a chaperone protein, can interplay with heat shock 70 protein ( Hsp70 ) and play important roles in organism’s response to heat stress (Corduan et al, 2009; Echevarría-Zomeño et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Identification and Evaluation of New Reference Genes for Gene Expression Analysis Under Temperature and Salinity Stresses in Ciona savignyi

Huang

Zhan

2019

Front. Genet.

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Rapid adaptation/accommodation to changing environments largely contributes to maximal survival of invaders during biological invasions, usually leading to success in crossing multiple barriers and finally in varied environments in recipient habitats. Gene expression is one of the most important and rapid ways during responses to environmental stresses. Selection of proper reference genes is the crucial prerequisite for gene expression analysis using the common approach, real-time quantitative PCR (RT-qPCR). Here we identified eight candidate novel reference genes from the RNA-Seq data in an invasive model ascidian Ciona savignyi under temperature and salinity stresses. Subsequently, the expression stability of these eight novel reference genes, as well as other six traditionally used reference genes, was evaluated using RT-qPCR and comprehensive tool RefFinder. Under the temperature stress, two traditional reference genes, ribosomal proteins S15 and L17 ( RPS15, RPL17 ), and one novel gene Ras homolog A ( RhoA ), were recommended as the top three stable genes, which can be used to normalize target genes with a high and moderate expression level, respectively. Under the salinity stress, transmembrane 9 superfamily member ( TMN ), MOB kinase activator 1A-like gene ( MOB ) and ubiquitin-conjugating enzyme ( UBQ2 ) were suggested as the top three stable genes. On the other hand, several commonly used reference genes such as α-tubulin ( TubA ), β-tubulin ( TubB ) and glyceraldehyde-3-phosphate dehydrogenase ( GAPDH ) showed unstable expressions, thus these genes should not be used as internal controls for gene expression analysis. We also tested the expression level of an important stress response gene, large proline-rich protein bag6-like gene ( BAG ) using different reference genes. As expected, we observed different results and conclusions when using different normalization methods, thus suggesting the importance of selection of proper reference genes and associated normalization methods. Our results provide a valuable reference gene resource for the normalization of gene expression in the study of environmental adaptation/accommodation during biological invasions using C. savignyi as a model.

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“…Proteasome-generated peptides of certain sizes are transported to the endoplasmic reticulum, where they bind to transporters associated with antigen processing (TAPs, TAP1 and TAP2) and assemble in a complex with ␤ 2 -microglobulin and the heavy chain of MHC class I. Assembly of peptide-MHC class I with TAPs is stabilized by tapasin and chaperones, allowing optimal MHC class I loading (9,11). These complexes are trafficked via the trans-Golgi to the plasma membrane, where they are recognized by the T lymphocyte cell receptor (TCR) (13,18).…”

Section: Introductionmentioning

confidence: 99%

Acetaldehyde suppresses the display of HBV-MHC class I complexes on HBV-expressing hepatocytes

Ganesan

Krutik

Makarov

et al. 2019

American Journal of Physiology-Gastrointestinal and Liver Physi

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Hepatitis B virus (HBV) infection and alcoholism are major public health problems worldwide, contributing to the development of end-stage liver disease. Alcohol intake affects HBV infection pathogenesis and treatment outcomes. HBV-specific cytotoxic T lymphocytes (CTLs) play an important role in HBV clearance. Many previous studies have focused on alcohol-induced impairments of the immune response. However, it is not clear whether alcohol alters the presentation of HBV peptide-major histocompatibility complex (MHC) class I complexes on infected hepatocytes resulting in escape of its recognition by CTLs. Hence, the focus of this study was to investigate the mechanisms by which ethanol metabolism affects the presentation of CTL epitope on HBV-infected hepatocytes. As demonstrated here, although continuous cell exposure to acetaldehyde-generating system (AGS) increased HBV load in HepG2.2.15 cells, it decreased the expression of HBV core peptide 18–27-human leukocyte antigen-A2complex (CTL epitope) on the cell surface. Moreover, we observed AGS-induced suppression of chymotrypsin- and trypsin-like proteasome activities necessary for peptide processing by proteasome as well as a decline in IFNγ-stimulated immunoproteasome (IPR) function and expression of PA28 activator and immunoproteasome subunits LMP7 and LMP2. Furthermore, IFNγ-induced activation of peptide-loading complex (PLC) components, such as transporter associated with antigen processing (TAP1) and tapasin, were suppressed by AGS. The attenuation of IPR and PLC activation was attributed to AGS-triggered impairment of IFNγ signaling in HepG2.2.15 cells. Collectively, all these downstream events reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, which may suppress CTL activation and the recognition of CTL epitopes on HBV-expressing hepatocytes by immune cells, thereby leading to persistence of liver inflammation. NEW & NOTEWORTHY Our study shows that in HBV-expressing HepG2.2.15 cells, acetaldehyde alters HBV peptide processing by suppressing chymotrypsin- and trypsin-like proteasome activities and decreases IFNγ-stimulated immunoproteasome function and expression of PA28 activator and immunoproteasome subunits. It also suppresses IFNγ-induced activation of peptide-loading complex (PLC) components due to impairment of IFNγ signaling via the JAK-STAT1 pathway. These acetaldehyde-induced dysfunctions reduced the display of HBV peptide-MHC class I complexes on the hepatocyte surface, thereby leading to persistence of HBV infection.

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Chaperone BAG6 is dispensable for MHC class I antigen processing and presentation

Cited by 11 publications

References 37 publications

Elimination of a signal sequence-uncleaved form of defective HLA protein through BAG6

Elimination of a signal sequence-uncleaved form of defective HLA protein through BAG6

Genome-Wide Identification and Evaluation of New Reference Genes for Gene Expression Analysis Under Temperature and Salinity Stresses in Ciona savignyi

Acetaldehyde suppresses the display of HBV-MHC class I complexes on HBV-expressing hepatocytes

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