Lipid peroxidation causes endosomal antigen release for cross-presentation

Dingjan, Ilse; Verboogen, Daniëlle R J; Paardekooper, Laurent M.; Revelo, Natalia H.; Sittig, Simone P.; Visser, Lenneke de; Mollard, Gabriele Fischer von; Henriet, Stefanie; Figdor, Carl G.; Beest, Martin ter; Bogaart, Geert van den

doi:10.1038/srep22064

Cited by 127 publications

(176 citation statements)

References 65 publications

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“…Mouse MCOLN1 residues 1–68 were generated as a synthetic gene in the XhoI/BamHI sites of pEGFP-C1. Transfection was performed as described (Baranov et al., 2014, Dingjan et al., 2016) and zymosan uptake and imaging experiments were performed 8–12 hr post-transfection.…”

Section: Methodsmentioning

confidence: 99%

SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis

et al. 2016

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SummaryActin plays a critical role during the early stages of pathogenic microbe internalization by immune cells. In this study, we identified a key mechanism of actin filament tethering and stabilization to the surface of phagosomes in human dendritic cells. We found that the actin-binding protein SWAP70 is specifically recruited to nascent phagosomes by binding to the lipid phosphatidylinositol (3,4)-bisphosphate. Multi-color super-resolution stimulated emission depletion (STED) microscopy revealed that the actin cage surrounding early phagosomes is formed by multiple concentric rings containing SWAP70. SWAP70 colocalized with and stimulated activation of RAC1, a known activator of actin polymerization, on phagosomes. Genetic ablation of SWAP70 impaired actin polymerization around phagosomes and resulted in a phagocytic defect. These data show a key role for SWAP70 as a scaffold for tethering the peripheral actin cage to phagosomes.

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Section: Methodsmentioning

confidence: 99%

SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis

et al. 2016

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“…If Sec61 is not involved, how then do antigens escape endocytic compartments in DCs? Recent studies suggest a role for reactive oxygen species and lipid peroxidation, which could locally destabilize the membrane of endocytic compartments, causing transient "leakage" into the cytosol (32). Local destabilization of the ER membrane through formation of lipid bodies was suggested a few years ago to mediate ERAD (33).…”

Section: Discussionmentioning

confidence: 99%

Sec61 blockade by mycolactone inhibits antigen cross-presentation independently of endosome-to-cytosol export

Grotzke

Kozik

Morel

et al. 2017

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

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Although antigen cross-presentation in dendritic cells (DCs) is critical to the initiation of most cytotoxic immune responses, the intracellular mechanisms and traffic pathways involved are still unclear. One of the most critical steps in this process, the export of internalized antigen to the cytosol, has been suggested to be mediated by Sec61. Sec61 is the channel that translocates signal peptide-bearing nascent polypeptides into the endoplasmic reticulum (ER), and it was also proposed to mediate protein retrotranslocation during ER-associated degradation (a process called ERAD). Here, we used a newly identified Sec61 blocker, mycolactone, to analyze Sec61's contribution to antigen cross-presentation, ERAD, and transport of internalized antigens into the cytosol. As shown previously in other cell types, mycolactone prevented protein import into the ER of DCs. Mycolactone-mediated Sec61 blockade also potently suppressed both antigen cross-presentation and direct presentation of synthetic peptides to CD8 + T cells. In contrast, it did not affect protein export from the ER lumen or from endosomes into the cytosol, suggesting that the inhibition of cross-presentation was not related to either of these trafficking pathways. Proteomic profiling of mycolactoneexposed DCs showed that expression of mediators of antigen presentation, including MHC class I and β2 microglobulin, were highly susceptible to mycolactone treatment, indicating that Sec61 blockade affects antigen cross-presentation indirectly. Together, our data suggest that the defective translocation and subsequent degradation of Sec61 substrates is the cause of altered antigen cross-presentation in Sec61-blocked DCs.Sec61 | cross-presentation | ERAD | mycolactone

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“…However, the mechanisms that cause phagosomal destabilization aren’t understood and absent this information, it is difficult to interrogate the contribution of this process to XPT. In theory, the oxidative burst, could destabilize phagosomes via lipid peroxidation which has been suggested to contribute to XPT (108). In fact, the loss of an enzyme that generates ROS (the NADPH oxidase, NOX2) impairs XPT in some (108, 109) but not all systems (unpublished data).…”

Section: Mechanism Of P2c Transfer Of Antigensmentioning

confidence: 99%

The Biology and Underlying Mechanisms of Cross-Presentation of Exogenous Antigens on MHC-I Molecules

Cruz

Colbert²,

Merino³

et al. 2017

Annu. Rev. Immunol.

232

228

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To monitor the health of cells, the immune system tasks antigen presenting cells with gathering antigens from other cells and reporting them to CD8 T cells in the form of peptides bound to MHC I molecules. Most cells would be unable to perform this function because they use their MHC I molecules to exclusively present peptides derived from the cell’s own proteins. However, the immune system evolved mechanisms for dendritic cells and some other phagocytes to sample and present antigens from the extracellular milieu on MHC I through a process called cross-presentation (XPT). How this important task is accomplished, its role in health and disease and its potential for exploitation are the subject of this review.

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Lipid peroxidation causes endosomal antigen release for cross-presentation

Cited by 127 publications

References 65 publications

SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis

SWAP70 Organizes the Actin Cytoskeleton and Is Essential for Phagocytosis

Sec61 blockade by mycolactone inhibits antigen cross-presentation independently of endosome-to-cytosol export

The Biology and Underlying Mechanisms of Cross-Presentation of Exogenous Antigens on MHC-I Molecules

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