EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling
Open accessPublished version of a preprint
Abstract
EROS (essential for reactive oxygen species) protein is indispensable for expression of gp91 phox , the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease, but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91 phox maturation. It binds the immature 58 kDa gp91 phox directly, preventing gp91 phox degradation and allowing glycosylation via the oligosaccharyltransferase machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions, and P2X7 is almost absent in EROS-deficient mouse and human primary cells. Accordingly, lack of murine EROS results in markedly abnormal P2X7 signalling, inflammasome activation, and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection in mice. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation, and possibly gene therapy.
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2 retracted
Martinez, J., Malireddi, R. K. S., Lu, Q., Cunha, L. D., Pelletier, S., Gingras, S., Orchard, R., Guan, J.-L., Tan, H., Peng, J., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3192 · Cited by 758 · cited 1× · see citing works
“…as inflammasome activation (Meissner et al., 2010), type 1 interferon production (Holmdahl et al., 2016, Sareila et al., 2017, Olsson et al., 2017, Zhong et al., 2018), LC3-associated phagocytosis (Martinez et al., 2015, Martinez et al., 2016) and autophagy (Thomas, 2018, de Luca et al., 2014).”
BackgroundRetractedMartinez, J., Cunha, L. D., Park, S., Yang, M., Lu, Q., Orchard, R., Li, Q.-Z., Yan, M., Janke, L., Guy, C., et al. (2016) · Nature · doi:10.1038/nature17950 · Cited by 381 · see citing works
RetractedHighly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Highly accurate protein structure prediction for the human proteome
Tunyasuvunakool, K., Adler, J., Wu, Z., Green, T., Zielinski, M., Žídek, A., Bridgland, A., Cowie, A., Meyer, C., Laydon, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03828-1 · Cited by 3,025 · cited 2× · see citing works
“, 2021) is available through the AlphaFold Protein Structure Database (Tunyasuvunakool et al., 2021).”
MethodInfluentialSelf-citationNanoLuc Complementation Reporter Optimized for Accurate Measurement of Protein Interactions in Cells
Dixon, A. S., Schwinn, M. K., Hall, M. P., Zimmerman, K., Otto, P., Lubben, T. H., Butler, B. L., Binkowski, B. F., Machleidt, T., Kirkland, T. A., et al. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.5b00753 · Cited by 1,405 · see citing works
Two cytosolic neutrophil oxidase components absent in autosomal chronic granulomatous disease
Volpp, B. D., Nauseef, W. M., & Clark, R. A. (1988) · Science · doi:10.1126/science.2848318 · Cited by 407 · see citing works
Wilgenburg, B. V., Browne, C., Vowles, J., & Cowley, S. A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0071098 · Cited by 353 · see citing works
de Luca, A., Smeekens, S. P., Casagrande, A., Iannitti, R., Conway, K. L., Gresnigt, M. S., Begun, J., Plantinga, T. S., Joosten, L. A. B., van der Meer, J. W. M., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1322831111 · Cited by 313 · see citing works
Wientjes, F. B., Hsuan, J. J., Totty, N. F., & Segal, A. W. (1993) · Biochemical Journal · doi:10.1042/bj2960557 · Cited by 301 · see citing works
Segal, A. W., Heyworth, P. G., Cockcroft, S., & Barrowman, M. M. (1985) · Nature · doi:10.1038/316547a0 · Cited by 281 · see citing works
Nrros negatively regulates reactive oxygen species during host defence and autoimmunity
Noubade, R., Wong, K., Ota, N., Rutz, S., Eidenschenk, C., Valdez, P. A., Ding, J., Peng, I., Sebrell, A., Caplazi, P., et al. (2014) · Nature · doi:10.1038/nature13152 · Cited by 246 · see citing works
Endosomal nox2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy
To, E. E., Vlahos, R., Luong, R., Halls, M. L., Reading, P. C., King, P. T., Chan, C., Drummond, G. R., Sobey, C. G., Broughton, B. R. S., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00057-x · Cited by 154 · see citing works
<b>T</b> <sub> <b>RM</b> </sub> <b>maintenance is regulated by tissue damage via P2RX7</b>
Stark, R., Wesselink, T. H., Behr, F. M., Kragten, N. A. M., Arens, R., Koch-Nolte, F., van Gisbergen, K. P. J. M., & van Lier, R. A. W. (2018) · Science Immunology · doi:10.1126/sciimmunol.aau1022 · Cited by 141 · cited 1× · see citing works
“P2X7 is crucial for ATPdriven activation of the NLRP3 inflammasome and has an emerging role in T cell biology, especially in resident immune cells (Stark, 2018).”
BackgroundNcf1 polymorphism reveals oxidative regulation of autoimmune chronic inflammation
Holmdahl, R., Sareila, O., Olsson, L. M., Bäckdahl, L., & Wing, K. (2016) · Immunological Reviews · doi:10.1111/imr.12378 · Cited by 131 · see citing works
Flagged first, then by citations
- Authors
- Randzavola, L. O., Mortimer, P. M., Garside, E., Dufficy, E. R., Schejtman, A., Roumelioti, G., Yu, L., Pardo, M., Spirohn, K., Tolley, C., Brandt, C., Harcourt, K., Nichols, E., Nahorski, M., Woods, G., Williamson, J. C., Suresh, S., Sowerby, J. M., Matsumoto, M., Santos, C. X., Kiar, C. S., Mukhopadhyay, S., Rae, W. M., Dougan, G. J., Grainger, J., Lehner, P. J., Calderwood, M. A., Choudhary, J., Clare, S., Speak, A., Santilli, G., Bateman, A., Smith, K. G., Magnani, F., & Thomas, D. C.
- Affiliations
- Imperial College London (GB)
- University of Cambridge (GB)
- University College London (GB)
- Institute of Cancer Research (GB)
- Harvard University (US)
- Wellcome Sanger Institute (GB)
- Kyoto Prefectural University of Medicine (JP)
- School of Cardiovascular Medicine and Sciences, James Black Centre, King's College London
- King's College London (GB)
- European Bioinformatics Institute (GB)
- University of Pavia (IT)
- Corresponding author
- Thomas, David C
- ORCID
- Randzavola, Lyra O
- Mortimer, Paige M
- Yu, Lu
- Pardo, Mercedes
- Spirohn, Kerstin
- Tolley, Charlotte
- Harcourt, Katherine
- Woods, Geoff
- Williamson, James C
- Suresh, Shreehari
- Sowerby, John M
- Matsumoto, Misaki
- Kiar, Cher Shen
- Mukhopadhyay, Subhankar
- Rae, William M
- Grainger, John
- Lehner, Paul J
- Calderwood, Michael A
- Choudhary, Jyoti
- Clare, Simon
- Speak, Anneliese
- Santilli, Giorgia
- Bateman, Alex
- Smith, Kenneth GC
- Magnani, Francesca
- Thomas, David C
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2022-11-24
- Volume
- 11
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC9767466
- OpenAlex
- W4309862298
- Cited by
- 24
- References
- 14
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 8 · 2023: 4 · 2022: 4
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (206617/A/17/Z)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- eros, gp91phox, NADPH oxidase, molecular chaperones, chronic granulomatous disease, purinergic signaling, P2X7 receptor, P2X1 receptor, oligosaccharyltransferase, protein glycosylation, heme incorporation, inflammasome activation, T cell response, reactive oxygen species, innate immunity, adaptive immunity
- MeSH terms
- Animals, Granulomatous Disease, Chronic, Humans, Phagocytes, Signal Transduction, Reactive Oxygen Species, NADPH Oxidases, Mice
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