Molluscum contagiosum virus MC80 sabotages MHC-I antigen presentation by targeting tapasin for ER-associated degradation

Harvey, Ian B.; Wang, Xiaoli; Fremont, Daved H.

doi:10.1371/journal.ppat.1007711

Cited by 22 publications

(12 citation statements)

References 82 publications

(95 reference statements)

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“…These findings implied that MC080 may be acting in the ER by direct sequestration or through competition for a factor required for HLA-I maturation. Further insight comes from a recent study that identifies an interaction between MC080 and tapasin as being critical in suppressing MHC-I maturation in murine cells [24]. Our observation that MC080 suppressed surface expression of HLA-A2.1 in TAP2-deficient human fibroblasts () would be consistent with this model if tapasin retained a substantial role in loading TAP-independent peptides on to HLA-A2 in TAP-negative fibroblasts.…”

Section: Discussionsupporting

confidence: 77%

“…When MC080 was expressed using a replication-competent vaccinia virus vector the protein was observed to accumulate in the ER and form a complex with ß−2 microglobulin, however its sequence was not thought to be compatible with peptide binding [23]. In a study undertaken in parallel with the one reported here, Harvey and co-workers recently reported that MC080 interacts with tapasin to impair cell-surface expression of MHC-I antigen [24].…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of HLA-I by the molluscum contagiosum virus mc080 impacts NK-cell recognition and promotes CD8+ T-cell evasion

Elasifer

Wang

Prod’homme

et al. 2020

Journal of General Virology

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Molluscum contagiosum virus (MCV) is a common cause of benign skin lesions in young children and currently the only endemic human poxvirus. Following the infection of primary keratinocytes in the epidermis, MCV induces the proliferation of infected cells and this results in the production of wart-like growths. Full productive infection is observed only after the infected cells differentiate. During this prolonged replication cycle the virus must avoid elimination by the host immune system. We therefore sought to investigate the function of the two major histocompatibility complex class-I-related genes encoded by the MCV genes mc033 and mc080. Following insertion into a replication-deficient adenovirus vector, codon-optimized versions of mc033 and mc080 were expressed as endoglycosidase-sensitive glycoproteins that localized primarily in the endoplasmic reticulum. MC080, but not MC033, downregulated cell-surface expression of endogenous classical human leucocyte antigen (HLA) class I and non-classical HLA-E by a transporter associated with antigen processing (TAP)-independent mechanism. MC080 exhibited a capacity to inhibit or activate NK cells in autologous assays in a donor-specific manner. MC080 consistently inhibited antigen-specific T cells being activated by peptide-pulsed targets. We therefore propose that MC080 acts to promote evasion of HLA-I-restricted cytotoxic T cells.

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Section: Discussionsupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Downregulation of HLA-I by the molluscum contagiosum virus mc080 impacts NK-cell recognition and promotes CD8+ T-cell evasion

Elasifer

Wang

Prod’homme

et al. 2020

Journal of General Virology

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“…Tapasin function can be targeted by viruses as a means of downmodulating HLA class I and evading cytotoxic CD8+ T cell (CTL) responses (20,21). Similarly, loss of tapasin expression has been observed in various human cancers (22).…”

Section: Significancementioning

confidence: 99%

HLA tapasin independence: broader peptide repertoire and HIV control

Bashirova

Viard

Naranbhai

et al. 2020

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

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Human leukocyte antigen (HLA) class I allotypes vary in their ability to present peptides in the absence of tapasin, an essential component of the peptide loading complex. We quantified tapasin dependence of all allotypes that are common in European and African Americans (n = 97), which revealed a broad continuum of values. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes, data supported by computational predictions. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level, like HLA zygosity, may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines.

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“…In particular, herpesviruses encode many proteins dedicated to the inhibition of TAP expression or function 34 . A recent study shows that tapasin becomes a degradation target in cells infected with molluscum contagiosum virus, thereby negatively affecting MHC-I assembly 37 . Somatic mutations of calreticulin have recently been reported in a subset of myeloproliferative neoplasms (MPNs).…”

Section: The Classical Mhc-i Assembly Pathway and Its Dysfunction In mentioning

confidence: 99%

Variations in MHC class I antigen presentation and immunopeptidome selection pathways

2020

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Major histocompatibility class I (MHC-I) proteins mediate immunosurveillance against pathogens and cancers by presenting antigenic or mutated peptides to antigen receptors of CD8+ T cells and by engaging receptors of natural killer (NK) cells. In humans, MHC-I molecules are highly polymorphic. MHC-I variations permit the display of thousands of distinct peptides at the cell surface. Recent mass spectrometric studies have revealed unique and shared characteristics of the peptidomes of individual MHC-I variants. The cell surface expression of MHC-I–peptide complexes requires the functions of many intracellular assembly factors, including the transporter associated with antigen presentation (TAP), tapasin, calreticulin, ERp57, TAP-binding protein related (TAPBPR), endoplasmic reticulum aminopeptidases (ERAPs), and the proteasomes. Recent studies provide important insights into the structural features of these factors that govern MHC-I assembly as well as the mechanisms underlying peptide exchange. Conformational sensing of MHC-I molecules mediates the quality control of intracellular MHC-I assembly and contributes to immune recognition by CD8 at the cell surface. Recent studies also show that several MHC-I variants can follow unconventional assembly routes to the cell surface, conferring selective immune advantages that can be exploited for immunotherapy.

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Molluscum contagiosum virus MC80 sabotages MHC-I antigen presentation by targeting tapasin for ER-associated degradation

Cited by 22 publications

References 82 publications

Downregulation of HLA-I by the molluscum contagiosum virus mc080 impacts NK-cell recognition and promotes CD8+ T-cell evasion

Downregulation of HLA-I by the molluscum contagiosum virus mc080 impacts NK-cell recognition and promotes CD8+ T-cell evasion

HLA tapasin independence: broader peptide repertoire and HIV control

Variations in MHC class I antigen presentation and immunopeptidome selection pathways

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