Cowpox Virus Exploits the Endoplasmic Reticulum Retention Pathway to Inhibit MHC Class I Transport to the Cell Surface

Byun, Minji; Wang, Xiaoli; Pak, Melissa; Hansen, Ted H.; Yokoyama, Wayne M.

doi:10.1016/j.chom.2007.09.002

Cited by 63 publications

(69 citation statements)

References 31 publications

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“…The complete alignment was done upon these sequences, and showed that all of these homologues contain the ER retrieval signal KDEL or RDEL. These tetrapeptides are responsible for the retention of proteins in the ER lumen (Munro & Pelham 1987;Persson et al 2005;Byun et al 2007), which suggested that BmGRP78 is an ERlocalized protein.…”

Section: Homology Analysis Of Bmgrp78mentioning

confidence: 99%

Molecular cloning and expression analysis of glucose-regulated protein 78 (GRP78) gene in silkworm Bombyx mori

Xing-zi

2013

Biologia

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GRP78 (78 kDa glucose-regulated protein), also known as BiP (immunoglobulin heavy-chain-binding protein), is an essential regulator of endoplasmic reticulum (ER) homeostasis because of its multiple functions in protein folding, ER calcium binding, and controlling of the activation of transmembrane ER stress sensors. In this report, we cloned the full-length cDNA of GRP78 from silkworm Bombyx mori (BmGRP78). It is 2645 bp, including an open reading frame (ORF) of 1977 bp encoding a polypeptide of 658 amino acids. We sequenced the ORF sequence from genomic DNA, and found only one intron (104 bp) existed in Bmgrp78 gene structure. The deduced amino acid sequence of Bmgrp78 carries the ER retention signal KDEL at its C-terminus and is highly homologous to GRP78 of Fenneropenaeus chinensis (83.59%) and Homo sapiens (80.27%). RT-PCR analysis shows that Bmgrp78 is ubiquitously expressed in tissues of silkworm. Heat shock over 35• C notably enhanced the expression of Bmgrp78 in head tissues. In response to starvation, the transcript level of Bmgrp78 in head tissues was 2.8-fold (at WS stage) and 3.2-fold (at SD1 stage) higher than the control level, but it remained stable in the midgut tissues. After silkworms were challenged by bacteria, the relative expression level of Bmgrp78 in midgut was up-regulated and reached maximal level at 24 hour after injection, and remained higher level than that of controls at about 48 hour post challenge. We infer that BmGRP78 may play important roles in chaperoning, protein folding and immune function of silkworm.

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Section: Homology Analysis Of Bmgrp78mentioning

confidence: 99%

Molecular cloning and expression analysis of glucose-regulated protein 78 (GRP78) gene in silkworm Bombyx mori

Xing-zi

2013

Biologia

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“…Because CPXV has coevolved with its rodent hosts, CPXV infection of rodents is appropriate for study of orthopoxvirus-host interactions. Two endogenous viral proteins, CPXV12 and CPXV203, act synergistically to down-regulate MHC class I molecules during CPXV infection (12)(13)(14). CPXV12 binds to the peptide-loading complex and inhibits loading of optimal peptides, whereas CPXV203 retains fully assembled MHC class I molecules in the ER by hijacking the KDEL receptor-ER retention pathway.…”

Section: D8mentioning

confidence: 99%

Viral MHC class I inhibition evades CD8 ⁺ T-cell effector responses in vivo but not CD8 ⁺ T-cell priming

Gainey

Rivenbark

Cho³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Although viral MHC class I inhibition is considered a classic immuneevasion strategy, its in vivo role is largely unclear. Mutant cowpox virus lacking its MHC class I inhibitors is markedly attenuated during acute infection because of CD8 + T-cell-dependent control, but it was not known how CD8 + T-cell responses are affected. Interestingly, we found no major effect of MHC class I downregulation on priming of functional cowpox virus-specific CD8 + T cells. Instead, we demonstrate that, during acute infection in vivo, MHC class I down-regulation prevents primed virus-specific CD8 + T cells from recognizing infected cells and exerting effector responses to control the infection.immune response | orthopoxvirus | virus evasion C D8+ T cells play an essential role in the control of many virus infections (1). In naive hosts, there are low numbers of CD8 + T cells that express MHC class I-restricted T-cell receptors specific for particular viral peptides. During primary infection, virusencoded peptides displayed by MHC class I molecules can be recognized by virus-specific CD8 + T cells, which then are primed to expand clonally in number via rapid cell division and gain effector functions. They then traffic to areas of virus replication and recognize virally infected cells by virtue of MHC class I molecules displaying viral peptides. CD8+ T-cell effector responses aid in viral clearance by direct killing of infected cells and secretion of proinflammatory cytokines (2). Depletion of CD8 + T cells often reveals enhanced viral infection as manifested by increased viral replication, morbidity, and lethality, highlighting the importance of CD8 + T cells in host immune control of viral infections. Many viruses have evolved mechanisms to thwart MHC class I expression. In particular, herpesviruses encode multiple inhibitors that target diverse steps in the MHC class I biosynthesis and presentation pathway (3). These inhibitors can be grouped according to their functional effects on MHC class I biosynthesis, such as inhibitors of TAP (transporter associated with antigen processing), and retention of MHC class I molecules in the endoplasmic reticulum (ER), among others. Studies of these viral inhibitors have helped illuminate the mechanisms responsible for normal MHC class I biosynthesis, and it generally has been perceived that these viral mechanisms represent immune evasion from CD8 + T-cell control. Despite progress in dissecting the mechanisms of viral inhibition of MHC class I expression in vitro, the role of endogenous viral MHC class I inhibition during acute infection has been difficult to demonstrate in vivo. This difficulty can be attributed in part to inhibition by human-specific viruses, such as CMV, that do not productively infect small animals that would allow detailed in vivo analysis. However, many studies have been performed with murine cytomegalovirus (MCMV). For example, MCMVspecific CD8 + T-cell lines preferentially killed cells infected with an MCMV mutant lacking all three MHC class I immuneevasion genes (m0...

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“…CPXV has the largest genome in the orthopoxvirus genus (34) and contains several ORFs not found in either the VV or ECTV genome. This includes two ORFs, CPXV012 and CPXV203, that potently down-regulate the expression of MHC class I (35)(36)(37)(38). Although this might render the infected cell sensitive to NK cell-mediated lysis, CPXV also encodes another ORF, CPXV018, that binds in vitro with high affinity to the NKG2D activation receptor and blocks its recognition of ligands on target cells (39).…”

Section: Significancementioning

confidence: 99%

Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection

Pak-Wittel¹,

Yang²,

Sojka³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells provide in vivo control of orthopoxvirus infections in association with their expansion in the draining lymph node (LN), where they are normally very rare. The mechanism of this expansion is unclear. Herein, we determined that NK-cell depletion results in enhanced infection following footpad inoculation of cowpox virus, a natural pathogen of rodents. Following cowpox virus infection in normal mice, NK cells were greatly expanded in the draining LN, were not replicating, and displayed markers similar to splenic NK cells, suggesting specific recruitment of splenic NK cells rather than in situ proliferation. Moreover, NK-cell expansion was abrogated by prior injection of clodronate-loaded liposomes, indicating a role for subcapsular sinus macrophages. Furthermore, recruitment of transferred splenic NK cells to the draining LN was pertussis toxin-sensitive, suggesting involvement of chemokine receptors. Comprehensive analysis of chemokine mRNA expression in the draining LN following infection suggested the selective involvement of CCR2, CCR5, and/or CXCR3. Mice deficient for CCR2 or CCR5 had normal NK-cell recruitment, whereas CXCR3-deficient mice displayed a major defect, which was NK cell-intrinsic. Interestingly, both induction of transcripts for CXCR3 ligands (Cxcl9 and Cxcl10) and NK-cell recruitment required IFN-γ. These data indicate that NK-cell recruitment is mediated by subcapsular sinus macrophages, IFN-γ, and CXCR3 during orthopoxvirus infection.

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Cowpox Virus Exploits the Endoplasmic Reticulum Retention Pathway to Inhibit MHC Class I Transport to the Cell Surface

Cited by 63 publications

References 31 publications

Molecular cloning and expression analysis of glucose-regulated protein 78 (GRP78) gene in silkworm Bombyx mori

Molecular cloning and expression analysis of glucose-regulated protein 78 (GRP78) gene in silkworm Bombyx mori

Viral MHC class I inhibition evades CD8 ⁺ T-cell effector responses in vivo but not CD8 ⁺ T-cell priming

Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection

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Cowpox Virus Exploits the Endoplasmic Reticulum Retention Pathway to Inhibit MHC Class I Transport to the Cell Surface

Cited by 63 publications

References 31 publications

Molecular cloning and expression analysis of glucose-regulated protein 78 (GRP78) gene in silkworm Bombyx mori

Molecular cloning and expression analysis of glucose-regulated protein 78 (GRP78) gene in silkworm Bombyx mori

Viral MHC class I inhibition evades CD8 + T-cell effector responses in vivo but not CD8 + T-cell priming

Interferon-γ mediates chemokine-dependent recruitment of natural killer cells during viral infection

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Viral MHC class I inhibition evades CD8 ⁺ T-cell effector responses in vivo but not CD8 ⁺ T-cell priming