The
            <scp>GTP</scp>
            ase Rab39a promotes phagosome maturation into
            <scp>MHC</scp>
            ‐I antigen‐presenting compartments

Cruz, Freidrich M.; Colbert, Jeff D.; Rock, Kenneth L.

doi:10.15252/embj.2019102020

Cited by 30 publications

(23 citation statements)

References 88 publications

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“…T cell division was assessed by CFSE dilution using flow cytometry. For cross presentation experiments with ISCOMATRIX™ adjuvant, 2x10 5 BMDCs were incubated with OVA in media that did or did not contain 10% ISCOMATRIX™ adjuvant for 4 hours, fixed with 1% PFA, and then incubated with 2x10 5 purified CFSE-labeled OT-I CD8+ T cells. For antibodydelivered cross presentation studies, 5x10 4 transduced BMDCs were incubated with 1 μg/ml αDEC205-OVA for 1 hour, washed twice, and incubated with 2x10 5 purified CFSE-labeled OT-I CD8+ T cells for 48 hours.…”

Section: Antigen Presentation Assaysmentioning

confidence: 99%

“…Whereas CTLs can be primed by direct presentation on MHC class I, cross presentation allows for the generation of adaptive immunity to exogenous antigens not expressed by antigen presenting cells (APCs). Although some cross presentation can occur within the phagosome itself [3][4][5], it is far more common for cross presented antigen to escape from phagosomes to be processed in the cytosol by proteasomal proteolysis with the resulting peptides transported into the ER via the TAP1/ TAP2 complex and loaded onto MHC class I molecules [6,7]. Owing partly to phagosomes characterized by higher pH, reduced enzymatic activity, and antigen preservation [8][9][10][11], DCs are particularly efficient at endosome to cytosol transfer (ECT) of antigen [12,13], yet how this process occurs remains a mystery.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Aquaporin-3 regulates endosome-to-cytosol transfer via lipid peroxidation for cross presentation

Nalle¹,

Silva²,

Zhang³

et al. 2020

PLoS ONE

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Antigen cross presentation, whereby exogenous antigens are presented by MHC class I molecules to CD8+ T cells, is essential for generating adaptive immunity to pathogens and tumor cells. Following endocytosis, it is widely understood that protein antigens must be transferred from endosomes to the cytosol where they are subject to ubiquitination and proteasome degradation prior to being translocated into the endoplasmic reticulum (ER), or possibly endosomes, via the TAP1/TAP2 complex. Revealing how antigens egress from endocytic organelles (endosome-to-cytosol transfer, ECT), however, has proved vexing. Here, we used two independent screens to identify the hydrogen peroxide-transporting channel aquaporin-3 (AQP3) as a regulator of ECT. AQP3 overexpression increased ECT, whereas AQP3 knockout or knockdown decreased ECT. Mechanistically, AQP3 appears to be important for hydrogen peroxide entry into the endosomal lumen where it affects lipid peroxidation and subsequent antigen release. AQP3-mediated regulation of ECT was functionally significant, as AQP3 modulation had a direct impact on the efficiency of antigen cross presentation in vitro. Finally, AQP3-/- mice exhibited a reduced ability to mount an anti-viral response and cross present exogenous extended peptide. Together, these results indicate that the AQP3-mediated transport of hydrogen peroxide can regulate endosomal lipid peroxidation and suggest that compromised membrane integrity and coordinated release of endosomal cargo is a likely mechanism for ECT.

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Section: Antigen Presentation Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Aquaporin-3 regulates endosome-to-cytosol transfer via lipid peroxidation for cross presentation

Nalle¹,

Silva²,

Zhang³

et al. 2020

PLoS ONE

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“…Rab GTPases and soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) tethers are master regulators of vesicular trafficking (Stenmark, 2009). Several factors have been reported to interfere with phagosome maturation and cross-presentation in DCs: Rab27a that brings NADPH oxidase 2 (NOX2)-containing vesicles to the phagosome (Jancic et al, 2007); Rab39a regulating ER-Golgi-to-phagosome transport and stabilizing phagosomal NOX2 and MHC-I molecules (Cruz et al, 2020); Rab3b/c (Zou et al, 2009), Rab11, and Rab22 involved in Toll-like receptor (TLR)-triggered MHC-I delivery to phagosome (Nair-Gupta et al, 2014); Rab34 inducing lysosomal clustering to the perinuclear region (Alloatti et al, 2015); and Rab43, a Golgi-related Rab controlling cross-presentation of phagocytized antigen in vivo (Kretzer et al, 2016). The SNARE protein Sec22b, by interaction with Stx4 on phagosomes, has been suggested to supply the latter with components of the peptide-loading complex and facilitate cross-presentation, although this role has been challenged by a second group using an in vivo model (Montealegre and van Endert, 2017;Wu et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

IRAP Endosomes Control Phagosomal Maturation in Dendritic Cells

Weimershaus

Mauvais

Evnouchidou

et al. 2020

Front. Cell Dev. Biol.

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Dendritic cells (DCs) contribute to the immune surveillance by sampling their environment through phagocytosis and endocytosis. We have previously reported that, rapidly following uptake of extracellular antigen into phagosomes or endosomes in DCs, a specialized population of storage endosomes marked by Rab14 and insulin-regulated aminopeptidase (IRAP) is recruited to the nascent antigen-containing compartment, thereby regulating its maturation and ultimately antigen cross-presentation to CD8+ T lymphocytes. Here, using IRAP–/– DCs, we explored how IRAP modulates phagosome maturation dynamics and cross-presentation. We find that in the absence of IRAP, phagosomes acquire more rapidly late endosomal markers, are more degradative, and show increased microbicidal activity. We also report evidence for a role of vesicle trafficking from the endoplasmic reticulum (ER)–Golgi intermediate compartment to endosomes for the formation or stability of the IRAP compartment. Moreover, we dissect the dual role of IRAP as a trimming peptidase and a critical constituent of endosome stability. Experiments using a protease-dead IRAP mutant and pharmacological IRAP inhibition suggest that IRAP expression but not proteolytic activity is required for the formation of storage endosomes and for DC-typical phagosome maturation, whereas proteolysis is required for fully efficient cross-presentation. These findings identify IRAP as a key factor in cross-presentation, trimming peptides to fit the major histocompatibility complex class-I binding site while preventing their destruction through premature phagosome maturation.

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“…Although some cross presentation can occur within the phagosome itself (5)(6)(7), it is far more common for cross presented antigen to escape from phagosomes to be processed in the cytosol by proteasomal proteolysis with the resulting peptides transported into the ER via the TAP1/TAP2 complex and loaded onto MHC class I molecules. Owing partly to phagosomes characterized by higher pH, reduced enzymatic activity, and antigen preservation (8)(9)(10)(11), DCs are particularly efficient at endosome to cytosol transfer (ECT) of antigen (12,13), yet how this process occurs remains a mystery.…”

Section: Introductionmentioning

confidence: 99%

Aquaporin-3 regulates endosome-to-cytosol transfer via lipid peroxidation for cross presentation

Nalle¹,

Silva²,

Zhang³

et al. 2020

Preprint

View full text Add to dashboard Cite

Antigen cross presentation, whereby exogenous antigens are presented by MHC class I molecules to CD8+ T cells, is essential for generating adaptive immunity to pathogens and tumor cells. Following endocytosis, it is widely understood that protein antigens must be transferred from endosomes to the cytosol where they are subject to ubiquitination and proteasome degradation prior to being translocated into the endoplasmic reticulum (ER), or possibly endosomes, via the TAP1/TAP2 complex. Revealing how antigens egress from endocytic organelles (endosome-to-cytosol transfer, ECT), however, has proved vexing. Here, we used two independent screens to identify the hydrogen peroxide-transporting channel aquaporin-3 (AQP3) as a regulator of ECT. AQP3 overexpression increased ECT, whereas AQP3 knockout or knockdown decreased ECT. Mechanistically, AQP3 appears to be important for hydrogen peroxide entry into the endosomal lumen where it affects lipid peroxidation and subsequent antigen release. AQP3-mediated regulation of ECT was functionally significant, as AQP3 modulation had a direct impact on the efficiency of antigen cross presentation in vitro . Finally, AQP3 -/- mice exhibited a reduced ability to mount an anti-viral response and cross present exogenous extended peptide. Together, these results indicate that the AQP3-mediated transport of hydrogen peroxide can regulate endosomal lipid peroxidation and suggest that compromised membrane integrity and coordinated release of endosomal cargo is a likely mechanism for ECT.

show abstract

The GTP ase Rab39a promotes phagosome maturation into MHC ‐I antigen‐presenting compartments

Cited by 30 publications

References 88 publications

Aquaporin-3 regulates endosome-to-cytosol transfer via lipid peroxidation for cross presentation

Aquaporin-3 regulates endosome-to-cytosol transfer via lipid peroxidation for cross presentation

IRAP Endosomes Control Phagosomal Maturation in Dendritic Cells

Aquaporin-3 regulates endosome-to-cytosol transfer via lipid peroxidation for cross presentation

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