MARCH9‐mediated ubiquitination regulates MHC I export from the TGN

Rigotti, Francesca; Gassart, Aude De; Pforr, Carina; Cano, Florencia; N’Guessan, Prudence; Combes, Alexis J.; Camossetto, Voahirana; Lehner, Paul J.; Pierre, Philippe; Gatti, Evelina

doi:10.1038/icb.2017.44

Cited by 36 publications

(25 citation statements)

References 34 publications

(70 reference statements)

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“…MKRN1 is first identified as a RING finger E3 ligase that regulates the degradation of hTERT through UPS (17). Many other E3 ligases are also involved in UPS, like MARCH9, cIAP1/2, FAF1, and TRIM25 (38)(39)(40)(41), which bind to E2 and substrate, primarily provide the Ub chain to the substrate, facilitating the formation of an isopeptide; finally, the target protein is degraded into small peptide fragments by the 26S proteasome (23,42). E3s mediate the degradation of substrates associated with conserved structural domains, including two classes, the really interesting new gene (RING) family and the homology to the E6AP C terminus (HECT), although a few have a U box, which is structurally and functionally similar to the RING finger domain (43,44).…”

Section: Discussionmentioning

confidence: 99%

Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation

Wang

et al. 2018

J Virol

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Porcine circovirus type 2 (PCV2) capsid protein (Cap) is a unique structure protein that plays pivotal roles in the process of viral replication and pathogenesis. Herein, we characterized a putative porcine Makorin RING finger protein 1 (pMKRN1) variant, an N-terminal-truncated variant of putative full-size porcine MKRN1 which has a unique expression pattern resulting from the porcine gene and which interacts with PCV2 Cap. A domain mapping assay showed that the C terminus of pMKRN1 and fragments (amino acids 108 to 198) of Cap are required for this interaction. PCV2 transiently upregulated pMKRN1 in PK-15 cells, but persistent viral infection downregulated pMKRN1 in major pathological tissues of PCV2-infected piglets. Overexpression of pMKRN1 significantly inhibited the generation of progeny PCV2 via ubiquitination and degradation of Cap, whereas knockout of pMKRN1 blocked Cap degradation and promoted progeny virus replication. pMKRN1 specifically targeted PCV2 Cap lysine residues 164, 179, and 191 to induce polyubiquitination and subsequent degradation. Mutation of either of the three lysine residues in the Cap protein or mutation of the histidine at residue 243 within the RING finger domain of pMKRN1 abrogated the E3 ligase activity of pMKRN1, rendering cells incapable of inducing Cap ubiquitination and degradation. Consistent with this finding, a Cap ubiquitination-deficient PCV2 strain showed enhanced virus replication and produced severe histological lesions in the lung and lymph node tissues compared with wild-type PCV2. Taken together, the results presented here suggest that PCV2 downregulates the pMKRN1 variant to avoid pMKRN1-mediated Cap ubiquitination and degradation, thus promoting viral replication and pathogenesis in its targeted tissues. Porcine circovirus type 2 is the pathogen to which pigs are the most susceptible, causing immense economic losses in the global swine industry, but whether host cells have developed some strategies to prevent viral replication is still unclear. Here, we found that porcine MKRN1 (pMKRN1) was upregulated in the early stage of PCV2 infection and mediated the polyubiquitination and degradation of Cap protein to block PCV2 replication, yet persistent PCV2 infection downregulated pMKRN1 levels to avoid degradation, promoting viral replication and pathogenesis in its targeted tissues. These data present new insight into the molecular mechanisms underlying the antiviral effects of pMKRN1 E3 ligase during PCV2 infection and also suggest potential new control measures for PCV2 outbreaks.

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Section: Discussionmentioning

confidence: 99%

Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation

Wang

et al. 2018

J Virol

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“…7c ). In contrast, there was no difference in the surface expression of HLA-I, a known target of MARCH9 43 and CD1a, which traffics independently of MHC-II during MoDC maturation 44 . These results suggest that invasive Salmonella develops molecular mechanisms to specifically target MHC-II molecules (Supplementary Figure 11 ).…”

Section: Resultsmentioning

confidence: 84%

Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets

et al. 2018

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Non-typhoidal Salmonella (NTS) are highly prevalent food-borne pathogens. Recently, a highly invasive, multi-drug resistant S. Typhimurium, ST313, emerged as a major cause of bacteraemia in children and immunosuppressed adults, however the pathogenic mechanisms remain unclear. Here, we utilize invasive and non-invasive Salmonella strains combined with single-cell RNA-sequencing to study the transcriptome of individual infected and bystander monocyte-derived dendritic cells (MoDCs) implicated in disseminating invasive ST313. Compared with non-invasive Salmonella, ST313 directs a highly heterogeneous innate immune response. Bystander MoDCs exhibit a hyper-activated profile potentially diverting adaptive immunity away from infected cells. MoDCs harbouring invasive Salmonella display higher expression of IL10 and MARCH1 concomitant with lower expression of CD83 to evade adaptive immune detection. Finally, we demonstrate how these mechanisms conjointly restrain MoDC-mediated activation of Salmonella-specific CD4+ T cell clones. Here, we show how invasive ST313 exploits discrete evasion strategies within infected and bystander MoDCs to mediate its dissemination in vivo.

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“…Several alternative scenarios could be considered. The TGN might feed this compartment with fully conformed class I molecules arriving through the secretory pathway, using, for example, Syntaxin 6 + and Rab14 + TGN-derived vesicles (79, 80). Another hypothesis is the adaptation of the late endosomal recycling pathway described by Lucin and coworkers, where lysosomes would communicate with recycling endosomes that are in physical proximity, thereby providing an environment where class I molecules are sorted for peptide exchange and routing into the recycling pathway, or degradation.…”

Section: Discussionmentioning

confidence: 99%

Endocytic Recycling of MHC Class I Molecules in Non-professional Antigen Presenting and Dendritic Cells

Montealegre

Endert

2019

Front. Immunol.

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Major histocompatibility complex class I (MHC I) molecules are glycoproteins that display peptide epitopes at the cell surface of nucleated cells for recognition by CD8+ T cells. Like other cell surface receptors, MHC class I molecules are continuously removed from the surface followed by intracellular degradation or recycling to the cell surface, in a process likely involving active quality control the mechanism of which remains unknown. The molecular players and pathways involved in internalization and recycling have previously been studied in model cell lines such as HeLa. However, dendritic cells (DCs), which rely on a specialized endocytic machinery that confers them the unique ability to “cross”-present antigens acquired by internalization, may use distinct MHC I recycling pathways and quality control mechanisms. By providing MHC I molecules cross-presenting antigens, these pathways may play an important role in one of the key functions of DCs, priming of T cell responses against pathogens and tumors. In this review, we will focus on endocytic recycling of MHC I molecules in various experimental conditions and cell types. We discuss the organization of the recycling pathway in model cell lines compared to DCs, highlighting the differences in the recycling rates and pathways of MHC I molecules between various cell types, and their putative functional consequences. Reviewing the literature, we find that conclusive evidence for significant recycling of MHC I molecules in primary DCs has yet to be demonstrated. We conclude that endocytic trafficking of MHC class I in DCs remains poorly understood and should be further studied because of its likely role in antigen cross-presentation.

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MARCH9‐mediated ubiquitination regulates MHC I export from the TGN

Cited by 36 publications

References 34 publications

Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation

Porcine MKRN1 Modulates the Replication and Pathogenesis of Porcine Circovirus Type 2 by Inducing Capsid Protein Ubiquitination and Degradation

Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets

Endocytic Recycling of MHC Class I Molecules in Non-professional Antigen Presenting and Dendritic Cells

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