scholarly journals Role for ribosome-associated quality control in sampling proteins for MHC class I-mediated antigen presentation

2020 ◽  
Vol 117 (8) ◽  
pp. 4099-4108 ◽  
Author(s):  
Débora Broch Trentini ◽  
Matteo Pecoraro ◽  
Shivani Tiwary ◽  
Jürgen Cox ◽  
Matthias Mann ◽  
...  
Keyword(s):  
Quality Control ◽  
Antigen Presentation ◽  
Mammalian Cells ◽  
Adaptive Immune System ◽  
Messenger Rnas ◽  
Mhc I ◽  
Adaptive Immune ◽  
Ribosome Stalling ◽  
Endogenous Substrates ◽  
Insight Into

Mammalian cells present a fingerprint of their proteome to the adaptive immune system through the display of endogenous peptides on MHC-I complexes. MHC-I−bound peptides originate from protein degradation by the proteasome, suggesting that stably folded, long-lived proteins could evade monitoring. Here, we investigate the role in antigen presentation of the ribosome-associated quality control (RQC) pathway for the degradation of nascent polypeptides that are encoded by defective messenger RNAs and undergo stalling at the ribosome during translation. We find that degradation of model proteins by RQC results in efficient MHC-I presentation, independent of their intrinsic folding properties. Quantitative profiling of MHC-I peptides in wild-type and RQC-deficient cells by mass spectrometry showed that RQC substantially contributes to the composition of the immunopeptidome. Our results also identify endogenous substrates of the RQC pathway in human cells and provide insight into common principles causing ribosome stalling under physiological conditions.

Plant MicroRNAs Responsive to Fungal Infection

2014 ◽  
Vol 941-944 ◽  
pp. 1141-1145 ◽  
Author(s):  
Hui Li Zhang ◽  
Lin Chen ◽  
Wen Na Li ◽  
Li Li Wang ◽  
Hong Yu Xie
Keyword(s):  
Fungal Pathogens ◽  
High Throughput Sequencing ◽  
Adaptive Immune System ◽  
Messenger Rnas ◽  
Disease Mechanism ◽  
Adaptive Immune ◽  
Alternative Approach ◽  
Crop Disease ◽  
Transcriptional Gene Regulation ◽  
And Control

MicroRNAs (miRNAs) are endogenous small RNAs transcribed from non-coding DNA, which have the capacity to base pair with the target mRNAs (messenger RNAs) to repress their translation or resulted in cleavage. We have paid much attention on the DNA and its coded proteins, the discovery of miRNAs as gene negatively regulators has led to a fundamental change in understanding of post-transcriptional gene regulation in plants. Fungal pathogens infection is the main cause of most economic crops diseases. Unlike humans, plants don’t evolved to have a adaptive immune system, they protect themselves with a mechanism consists of activation and response. Recently, high throughput sequencing validated that miRNA play a crucial role in plant-fungus interaction. A better understanding of miRNA-mediated disease mechanism in fungi should clarify the strategy of crop disease control. MiRNA-based manipulations as gene suppressors, such as artificial miRNAs, may emerge as a new alternative approach for the improvement of crops and control of crop disease.

scholarly journals SARS-COV-2 acts as a test of Air Pollution, Lifestyle Disorders and Immune Tolerance dysregulation in human body

2021 ◽  
Author(s):  
bose Karthik
Keyword(s):  
Immune System ◽  
Immune Tolerance ◽  
Adaptive Immune System ◽  
Innate Immune ◽  
Human Immune System ◽  
Adaptive Immune ◽  
Human Immune ◽  
Humoral Responses ◽  
Skeletal Mechanism ◽  
Insight Into

SARS-COV-2 is reported to be associated with severe immune dysregulation, delayed humoral responses and accelerated innate immune response mediated damages. As the pandemic is turning the world upside down, In order to address this disease we should first get an insight into the mechanism of action through which SARS-COV-2 is achieving the above said dysregulating or modulating effects on human immune system. T his article presents the basic or skeletal mechanism through which SARS-COV-2 dysregulates immune system by targeting innate immune system, adaptive immune system and different immune tolerance check points by dysregulating different miRNA’s and the preexisting conditions or comorbidities of the patients. This article comprises of the comparative and comprehensive literature review targeting all topics with the data available/reported till date in the scientific community.

Better together: Alveolar macrophage and memory T cell cosignaling in ex vivo human lungs

2021 ◽  
Vol 13 (578) ◽  
pp. eabg5637
Author(s):  
Steven P. Keller
Keyword(s):  
Ex Vivo ◽  
Adaptive Immune System ◽  
Lung Perfusion ◽  
Ex Vivo Lung Perfusion ◽  
Memory T Cell ◽  
Adaptive Immune ◽  
Human Lungs ◽  
Insight Into ◽  
Pathogen Exposure ◽  
Lung Response

Ex vivo lung perfusion enables assessment of the resident adaptive immune system and provides insight into the lung response to pathogen exposure.

scholarly journals The role of dendritic and В-cells in the development of metainflammation of adipose tissue in obesity

2021 ◽  
Vol 16 (1) ◽  
pp. 60-74
Author(s):  
A.E. Abaturov ◽  
A.А. Nikulina
Keyword(s):  
Dendritic Cells ◽  
Adipose Tissue ◽  
Immune System ◽  
B Cells ◽  
Antigen Presentation ◽  
B Lymphocytes ◽  
Adaptive Immune System ◽  
Fine Tuning ◽  
Peripheral Tissues ◽  
Adaptive Immune

The literature review presents modern data on the spectrum of functional capabilities of the main dendritic cells and B-lymphocytes in the development of metainflammation of adipose tissue in obesity. Dendritic cells functionally link innate and adaptive immunity. The functioning of a subpopulation of professional antigen-presenting lymphocytes — dendritic cells determines the processing, antigen presentation, the canalization of cytodifferentiation of naive T-cells, the activation of B-lymphocytes and specific antibody response. The activation of dendritic cells in adipose tissue is largely due to the interaction of Toll-like receptors 2 and 4 of their cytoplasmic membrane with free fatty acids, the excess of which accompanies the process of obesity. Obesity against the background of experimental dendritic cell depletion in adipose tissue is accompanied by a low level of infiltration by proinflammatory macrophages of both adipose and liver tissue in combination with a higher level of insulin sensitivity of peripheral tissues. The data on the possibility of primary activation of the adaptive immune system in some special clusters of visceral adipose tissue are presented: the lymphoid cluster associated with adipose tissue and milky spots. Activated B-cells perform the function of antigen presentation and antibody formation in the development of the immune response and play an important regulatory role in fine tuning the functioning of the immune system. Thus, the data of most studies indicate that in the development of obesity, dendritic cells, in general, contribute to the development of metainflammation. Obesity leads to accumulation of B-2 cells in adipose tissue, more active production of B-cell-associated pro-inflammatory cytokines, and the generation of IgG, which recruits macrophages into adipose tissue. However, nume­rous questions about the regulation of recruiting, activation of dendritic cells and B-cells in the development of obesity remain unclear. In particular, factors are unknown that recruit tolerogenic dendritic and Breg cells, the mechanisms of regulation of their recruitment to different depots of adipose tissue and the possibility of activa­ting these cells, triggers of the synthesis of protective IgM antibodies. Antigens involved in the activation of the adaptive immune system in the development of obesity also remain unknown.

scholarly journals Recent advances in Major Histocompatibility Complex (MHC) class I antigen presentation: Plastic MHC molecules and TAPBPR-mediated quality control

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 158 ◽  
Author(s):  
Andy van Hateren ◽  
Alistair Bailey ◽  
Tim Elliott
Keyword(s):  
Quality Control ◽  
Major Histocompatibility Complex ◽  
Antigen Presentation ◽  
Mhc Class I ◽  
Class I ◽  
Major Histocompatibility ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Peptide Loading ◽  
Mhc Class I Molecules

We have known since the late 1980s that the function of classical major histocompatibility complex (MHC) class I molecules is to bind peptides and display them at the cell surface to cytotoxic T cells. Recognition by these sentinels of the immune system can lead to the destruction of the presenting cell, thus protecting the host from pathogens and cancer. Classical MHC class I molecules (MHC I hereafter) are co-dominantly expressed, polygenic, and exceptionally polymorphic and have significant sequence diversity. Thus, in most species, there are many different MHC I allotypes expressed, each with different peptide-binding specificity, which can have a dramatic effect on disease outcome. Although MHC allotypes vary in their primary sequence, they share common tertiary and quaternary structures. Here, we review the evidence that, despite this commonality, polymorphic amino acid differences between allotypes alter the ability of MHC I molecules to change shape (that is, their conformational plasticity). We discuss how the peptide loading co-factor tapasin might modify this plasticity to augment peptide loading. Lastly, we consider recent findings concerning the functions of the non-classical MHC I molecule HLA-E as well as the tapasin-related protein TAPBPR (transporter associated with antigen presentation binding protein-related), which has been shown to act as a second quality-control stage in MHC I antigen presentation.

Novel Mechanisms for Resolution of Liver Inflammation: Therapeutic Implications

2021 ◽  
Author(s):  
Benedikt Kaufmann ◽  
Agustina Reca ◽  
Andrea D. Kim ◽  
Ariel E. Feldstein
Keyword(s):  
Inflammatory Response ◽  
Adaptive Immune System ◽  
Hepatic Function ◽  
New Paradigm ◽  
Therapeutic Implications ◽  
Adaptive Immune ◽  
Disease States ◽  
Insight Into ◽  
Stimulation Of

AbstractTraditional concepts have classically viewed resolution of inflammation as a passive process yet insight into the pathways by which inflammation is resolved has challenged this idea. Resolution has been revealed as a highly dynamic and active event that is essential to counteract the dysregulated inflammatory response that drives diverse disease states. Abrogation of the hepatic inflammatory response through the stimulation of proresolving mechanisms represents a new paradigm in the setting of chronic inflammatory-driven liver diseases. Elucidation of the role of different cells of the innate and adaptive immune system has highlighted the interplay between them as an important orchestrator of liver repair. A finely tuned interaction between neutrophils and macrophages has risen as revolutionary mechanism that drives the restoration of hepatic function and architecture. Specialized proresolving mediators have also been shown to act as stop signals of the inflammatory response and promote resolution as well as tissue regeneration. In this review, we discuss the discovery and understanding of the mechanisms by which inflammation is resolved and highlight novel proresolving pathways that represent promising therapeutic strategies.

scholarly journals Readthrough of stop codons under limiting ABCE1 concentration involves frameshifting and inhibits nonsense-mediated mRNA decay

2020 ◽  
Vol 48 (18) ◽  
pp. 10259-10279
Author(s):  
Giuditta Annibaldis ◽  
Michal Domanski ◽  
René Dreos ◽  
Lara Contu ◽  
Sarah Carl ◽  
...  
Keyword(s):  
Quality Control ◽  
Mrna Decay ◽  
Translation Termination ◽  
Human Cells ◽  
Ribosome Recycling Factor ◽  
Ribosome Stalling ◽  
Endonucleolytic Cleavage ◽  
Nonsense Mediated Mrna Decay ◽  
Insight Into ◽  
Reading Frames

Abstract To gain insight into the mechanistic link between translation termination and nonsense-mediated mRNA decay (NMD), we depleted the ribosome recycling factor ABCE1 in human cells, resulting in an upregulation of NMD-sensitive mRNAs. Suppression of NMD on these mRNAs occurs prior to their SMG6-mediated endonucleolytic cleavage. ABCE1 depletion caused ribosome stalling at termination codons (TCs) and increased ribosome occupancy in 3′ UTRs, implying enhanced TC readthrough. ABCE1 knockdown indeed increased the rate of readthrough and continuation of translation in different reading frames, providing a possible explanation for the observed NMD inhibition, since enhanced readthrough displaces NMD activating proteins from the 3′ UTR. Our results indicate that stalling at TCs triggers ribosome collisions and activates ribosome quality control. Collectively, we show that improper translation termination can lead to readthrough of the TC, presumably due to ribosome collisions pushing the stalled ribosomes into the 3′ UTR, where it can resume translation in-frame as well as out-of-frame.

scholarly journals SAMHD1 Limits HIV-1 Antigen Presentation by Monocyte-Derived Dendritic Cells

2015 ◽  
Vol 89 (14) ◽  
pp. 6994-7006 ◽  
Author(s):  
Diana Ayinde ◽  
Timothée Bruel ◽  
Sylvain Cardinaud ◽  
Françoise Porrot ◽  
Julia G. Prado ◽  
...  
Keyword(s):  
Immune Responses ◽  
Antigen Presentation ◽  
Cytotoxic T Lymphocytes ◽  
Viral Proteins ◽  
Productive Infection ◽  
Restriction Factors ◽  
Adaptive Immune Responses ◽  
Mhc I ◽  
Adaptive Immune ◽  
Hiv 1

ABSTRACTMonocyte-derived dendritic cells (MDDC) stimulate CD8+cytotoxic T lymphocytes (CTL) by presenting endogenous and exogenous viral peptides via major histocompatibility complex class I (MHC-I) molecules. MDDC are poorly susceptible to HIV-1, in part due to the presence of SAMHD1, a cellular enzyme that depletes intracellular deoxynucleoside triphosphates (dNTPs) and degrades viral RNA. Vpx, an HIV-2/SIVsm protein absent from HIV-1, antagonizes SAMHD1 by inducing its degradation. The impact of SAMHD1 on the adaptive cellular immune response remains poorly characterized. Here, we asked whether SAMHD1 modulates MHC-I-restricted HIV-1 antigen presentation. Untreated MDDC or MDDC pretreated with Vpx were exposed to HIV-1, and antigen presentation was examined by monitoring the activation of an HIV-1 Gag-specific CTL clone. SAMHD1 depletion strongly enhanced productive infection of MDDC as well as endogenous HIV-1 antigen presentation. Time-lapse microscopy analysis demonstrated that in the absence of SAMHD1, the CTL rapidly killed infected MDDC. We also report that various transmitted/founder (T/F) HIV-1 strains poorly infected MDDC and, as a consequence, did not stimulate CTL. Vesicular stomatitis virus glycoprotein (VSV-G) pseudotyping of T/F alleviated a block in viral entry and induced antigen presentation only in the absence of SAMHD1. Furthermore, by using another CTL clone that mostly recognizes incoming HIV-1 antigens, we demonstrate that SAMHD1 does not influence exogenous viral antigen presentation. Altogether, our results demonstrate that the antiviral activity of SAMHD1 impacts antigen presentation by DC, highlighting the link that exists between restriction factors and adaptive immune responses.IMPORTANCEUpon viral infection, DC may present antigens derived from incoming viral material in the absence of productive infection of DC or from newly synthesized viral proteins. In the case of HIV, productive infection of DC is blocked at an early postentry step. This is due to the presence of SAMHD1, a cellular enzyme that depletes intracellular levels of dNTPs and inhibits viral reverse transcription. We show that the depletion of SAMHD1 in DCs strongly stimulates the presentation of viral antigens derived from newly produced viral proteins, leading to the activation of HIV-1-specific cytotoxic T lymphocytes (CTL). We further show in real time that the enhanced activation of CTL leads to killing of infected DCs. Our results indicate that the antiviral activity of SAMHD1 not only impacts HIV replication but also impacts antigen presentation by DC. They highlight the link that exists between restriction factors and adaptive immune responses.

scholarly journals Structural and functional studies of the decapping exoribonucleases

2014 ◽  
Vol 70 (a1) ◽  
pp. C1397-C1397
Author(s):  
Jeong Ho Chang ◽  
Liang Tong
Keyword(s):  
Quality Control ◽  
Mammalian Cells ◽  
Catalytic Mechanism ◽  
Control Mechanism ◽  
Normal Growth ◽  
Growth Conditions ◽  
Current Understanding ◽  
Messenger Rnas ◽  
End Capping ◽  
Quality Control Mechanism

Recent studies showed that two homologous yeast proteins, Rai1 and Dxo1, function in a quality control mechanism to clear cells of incompletely 5' end-capped messenger RNAs (mRNAs). Rai1 possesses a novel decapping activity that can remove the entire cap structure dinucleotide from an mRNA. This activity is targeted preferentially towards mRNAs with unmethylated caps in contrast to the canonical decapping enzyme, Dcp2, which targets mRNAs with a methylated cap. Dxo1 also has robust decapping activity on RNAs with unmethylated caps, but it has no detectable pyrophosphohydrolase activity. Unexpectedly, we found that Dxo1 also possesses distributive, 5'-3' exoribonuclease activity, and we named Dxo1 (originally Ydr370C) for this new eukaryotic enzyme with both decapping and exonuclease activities. Studies of yeast in which both Dxo1 and Rai1 are disrupted reveal that mRNAs with incomplete caps are produced even under normal growth conditions, in sharp contrast to current understanding of the capping process. Here, we introduce that their mammalian homolog, Dom3Z (referred to as DXO), possesses pyrophosphohydrolase, decapping, and 5'-3' exoribonuclease activities. Surprisingly, we found that DXO preferentially degrades defectively capped pre-mRNAs in cells. Additional studies show that incompletely capped pre-mRNAs are inefficiently spliced at all introns, a fact that contrasts with current understanding, and are also poorly cleaved for polyadenylation. Crystal structures of DXO in complex with substrate mimic and products at a resolution of up to 1.5 Å provide elegant insights into the catalytic mechanism and molecular basis for their three apparently distinct activities. Our data reveal a pre-mRNA 5' end capping quality control mechanism in mammalian cells, indicating DXO as the central player for this mechanism, and demonstrate an unexpected intimate link between proper 5' end capping and subsequent pre-mRNA processing.

scholarly journals Non-random association of MHC-I alleles in favor of high diversity haplotypes in wild songbirds revealed by computer-assisted MHC haplotype inference using the R package MHCtools

2020 ◽  
Author(s):  
Jacob Roved ◽  
Bengt Hansson ◽  
Martin Stervander ◽  
Dennis Hasselquist ◽  
Helena Westerdahl
Keyword(s):  
Immune System ◽  
Structural Organization ◽  
Adaptive Immune System ◽  
R Package ◽  
Future Research ◽  
Computer Assisted ◽  
Class I Mhc ◽  
Mhc I ◽  
Mhc Genes ◽  
Adaptive Immune

AbstractMajor histocompatibility complex (MHC) genes play a central role for pathogen recognition by the adaptive immune system. The MHC genes are often duplicated and tightly linked within a small genomic region. This structural organization suggests that natural selection acts on the combined property of multiple MHC gene copies in segregating haplotypes, rather than on single MHC genes. This may have important implications for analyses of patterns of selection on MHC genes. Here, we present a computer-assisted protocol to infer segregating MHC haplotypes from family data, based on functions in the R package MHCtools. We employed this method to identify 107 unique MHC class I (MHC-I) haplotypes in 116 families of wild great reed warblers (Acrocephalus arundinaceus). In our data, the MHC-I genes were tightly linked in haplotypes and inherited as single units, with only two observed recombination events among 334 offspring. We found substantial variation in the number of different MHC-I alleles per haplotype, and the divergence between alleles in MHC-I haplotypes was significantly higher than between randomly assigned alleles in simulated haplotypes. This suggests that selection has favored non-random associations of divergent MHC-I alleles in haplotypes to increase the range of pathogens that can be recognized by the adaptive immune system. Further studies of selection on MHC haplotypes in natural populations is an interesting avenue for future research. Moreover, inference and analysis of MHC haplotypes offers important insights into the structural organization of MHC genes, and may improve the accuracy of the MHC region in de novo genome assemblies.

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