Physiological substrates and ontogeny-specific expression of the ubiquitin ligases MARCH1 and MARCH8

Schriek, Patrick; Liu, Haiyin; Ching, Alan; Huang, Pauline; Gupta, Nishma; Wilson, Kayla R; Tsai, Meng-Chang; Yan, Yixin; Macri, Christophe; Dagley, Laura F.; Infusini, Giuseppe; Webb, Andrew I.; McWilliam, Hamish E G; Ishido, Satoshi; Mintern, Justine D.; Villadangos, José A

doi:10.1016/j.crimmu.2021.10.004

Cited by 7 publications

(5 citation statements)

References 75 publications

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“…Importantly, and supporting our T1D-related findings, it is known that macrophages from T1D patients with high-risk HLA-DQB1 alleles are sensitized to secrete IL-6 in response to nonantigenic stimulation (46). Interestingly, phosphorylated MARCH8 (gene symbol: MARCHF8), an E3 ubiquitin-protein ligase that regulates the expression and trafficking of critical immunoreceptors such as the MHC class II proteins (49, 50), specifically in non-hematopoietic cells (i.e., thymic and alveolar epithelial cells) (51), was also significantly downregulated in the circulating EV-enriched preparations.…”

Section: Discussionmentioning

confidence: 99%

The proteome and phosphoproteome of circulating extracellular vesicle-enriched preparations are associated with characteristic clinical features in type 1 diabetes

Casu,

Nunez Lopez,

et al. 2023

Front. Endocrinol.

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IntroductionThere are no validated clinical or laboratory biomarkers to identify and differentiate endotypes of type 1 diabetes (T1D) or the risk of progression to chronic complications. Extracellular vesicles (EVs) have been studied as biomarkers in several different disease states but have not been well studied in T1D.MethodsAs the initial step towards circulating biomarker identification in T1D, this pilot study aimed to provide an initial characterization of the proteomic and phosphoproteomic landscape of circulating EV-enriched preparations in participants with established T1D (N=10) and healthy normal volunteers (Controls) (N=7) (NCT03379792) carefully matched by age, race/ethnicity, sex, and BMI. EV-enriched preparations were obtained using EVtrap® technology. Proteins were identified and quantified by LC-MS analysis. Differential abundance and coexpression network (WGCNA), and pathway enrichment analyses were implemented.ResultsThe detected proteins and phosphoproteins were enriched (75%) in exosomal proteins cataloged in the ExoCarta database. A total of 181 proteins and 8 phosphoproteins were differentially abundant in participants with T1D compared to controls, including some well-known EVproteins (i.e., CD63, RAB14, BSG, LAMP2, and EZR). Enrichment analyses of differentially abundant proteins and phosphoproteins of EV-enriched preparations identified associations with neutrophil, platelet, and immune response functions, as well as prion protein aggregation. Downregulated proteins were involved in MHC class II signaling and the regulation of monocyte differentiation. Potential key roles in T1D for C1q, plasminogen, IL6ST, CD40, HLA-DQB1, HLA-DRB1, CD74, NUCB1, and SAP, are highlighted. Remarkably, WGCNA uncovered two protein modules significantly associated with pancreas size, which may be implicated in the pathogenesis of T1D. Similarly, these modules showed significant enrichment for membrane compartments, processes associated with inflammation and the immune response, and regulation of viral processes, among others.DiscussionThis study demonstrates the potential of proteomic and phosphoproteomic signatures of EV-enriched preparations to provide insight into the pathobiology of T1D. The WGCNA analysis could be a powerful tool to discriminate signatures associated with different pathobiological components of the disease.

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Section: Discussionmentioning

confidence: 99%

The proteome and phosphoproteome of circulating extracellular vesicle-enriched preparations are associated with characteristic clinical features in type 1 diabetes

Casu,

Nunez Lopez,

et al. 2023

Front. Endocrinol.

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“…The only receptors known to increase in expression in March1 –/– cDCs are MHC II and CD86 (fig. S2E) ( 2 ), but a recent plasma membrane proteome analysis showed that the surface of March1 –/– cDCs is also highly enriched in C3 ( 12 ). Because C3 is inaccessible to cytosolic ubiquitination by MARCH1, we sought to characterize the mechanism that caused its accumulation on the cell surface before investigating its potential role in trogocytosis.…”

Section: March1 Controls the Amount Of C3 That Accumulates On The Sur...mentioning

confidence: 99%

“…4A). MARCH1 is active in all hematopoietic APCs, where it keeps surface MHC II expression at intermediate to low levels ( 12 ). We observed an increase in C3 deposition on both professional and “atypical” APCs from the spleen, lymph nodes, and thymus but not on T cells (Fig.…”

Section: March1 Controls the Amount Of C3 That Accumulates On The Sur...mentioning

confidence: 99%

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Marginal zone B cells acquire dendritic cell functions by trogocytosis

Schriek

Ching

Moily

et al. 2022

Science

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Marginal zone (MZ) B cells produce broad-spectrum antibodies that protect against infection early in life. In some instances, antibody production requires MZ B cells to display pathogen antigens bound to major histocompatibility complex class II (MHC II) molecules to T cells. We describe the trogocytic acquisition of these molecules from conventional dendritic cells (cDCs). Complement component 3 (C3) binds to murine and human MHC II on cDCs. MZ B cells recognize C3 with complement receptor 2 (CR2) and trogocytose the MHC II–C3 complexes, which become exposed on their cell surface. The ubiquitin ligase MARCH1 limits the number of MHC II–C3 complexes displayed on cDCs to prevent their elimination through excessive trogocytosis. Capture of C3 by MHC II thus enables the transfer of cDC-like properties to MZ B cells.

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“…Newly formed cDCs are traditionally termed immature (8,100,101,117), but here we follow the recent recommendation to refer to them as resting (12), as this term is better aligned with the terminology applied to other cell types, including macrophages (Figure 1). Resting cDCs are characterized by high endocytic capacity, fast turnover of MHC-II molecules induced by ubiquitination (118,119) and low expression of T cell stimulatory or inhibitory receptors and cytokines (101,120,121). Most of the resting cDCs that develop within lymphoid organs die quickly (their half-life is three to five days) and without undergoing further developmental changes (104) (Figure 1).…”

Section: Cdc Migration and Maturation In The Steady Statementioning

confidence: 99%

Spatiotemporal Adaptations of Macrophage and Dendritic Cell Development and Function

Roquilly

Mintern

Villadangos

2022

Annu. Rev. Immunol.

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Macrophages and conventional dendritic cells (cDCs) are distributed throughout the body, maintaining tissue homeostasis and tolerance to self and orchestrating innate and adaptive immunity against infection and cancer. As they complement each other, it is important to understand how they cooperate and the mechanisms that integrate their functions. Both are exposed to commensal microbes, pathogens, and other environmental challenges that differ widely among anatomical locations and over time. To adjust to these varying conditions, macrophages and cDCs acquire spatiotemporal adaptations (STAs) at different stages of their life cycle that determine how they respond to infection. The STAs acquired in response to previous infections can result in increased responsiveness to infection, termed training, or in reduced responses, termed paralysis, which in extreme cases can cause immunosuppression. Understanding the developmental stage and location where macrophages and cDCs acquire their STAs, and the molecular and cellular players involved in their induction, may afford opportunities to harness their beneficial outcomes and avoid or reverse their deleterious effects. Here we review our current understanding of macrophage and cDC development, life cycle, function, and STA acquisition before, during, and after infection. We propose a unified framework to explain how these two cell types adjust their activities to changing conditions over space and time to coordinate their immunosurveillance functions. Expected final online publication date for the Annual Review of Immunology, Volume 40 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Physiological substrates and ontogeny-specific expression of the ubiquitin ligases MARCH1 and MARCH8

Cited by 7 publications

References 75 publications

The proteome and phosphoproteome of circulating extracellular vesicle-enriched preparations are associated with characteristic clinical features in type 1 diabetes

The proteome and phosphoproteome of circulating extracellular vesicle-enriched preparations are associated with characteristic clinical features in type 1 diabetes

Marginal zone B cells acquire dendritic cell functions by trogocytosis

Spatiotemporal Adaptations of Macrophage and Dendritic Cell Development and Function

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