Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity

Thomas, David; Clare, Simon; Sowerby, John M.; Pardo, Mercedes; Juss, Jatinder K.; Goulding, David; Weyden, Louise van der; Storisteanu, Daniel M. L.; Prakash, Ananth; Espéli, Marion; Flint, Shaun; Lee, James C.; Hoenderdos, Kim; Kane, Leanne; Harcourt, Katherine; Mukhopadhyay, Subhankar; Umrania, Yagnesh; Antrobus, Robin; Nathan, James A.; Adams, David J.; Bateman, Alex; Choudhary, Jyoti S.; Lyons, Paul; Condliffe, Alison M.; Chilvers, Edwin R.; Dougan, Gordon; Smith, Kenneth G. C.

doi:10.1084/jem.20161382

Cited by 57 publications

(66 citation statements)

References 55 publications

(94 reference statements)

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“…The brothers are the only members of their family homozygous for CYBC1 p.Tyr2Ter, their parents and two unaffected siblings are heterozygous carriers, and their third sibling a non-carrier (all confirmed by Sanger sequencing). CYBC1 shares 89% amino acid sequence identity with the murine bc017643 which was recently shown to be essential for ROS production 14 , consistent with the reduced ROS production described for CGD patients. Both neutrophils and BM-derived macrophages from bc017643 -knockout mice showed a highly impaired oxidative burst in response to a range of stimuli, including PMA.…”

Section: Resultssupporting

confidence: 76%

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease

et al. 2018

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Mutations in genes encoding subunits of the phagocyte NADPH oxidase complex are recognized to cause chronic granulomatous disease (CGD), a severe primary immunodeficiency. Here we describe how deficiency of CYBC1, a previously uncharacterized protein in humans (C17orf62), leads to reduced expression of NADPH oxidase’s main subunit (gp91phox) and results in CGD. Analyzing two brothers diagnosed with CGD we identify a homozygous loss-of-function mutation, p.Tyr2Ter, in CYBC1. Imputation of p.Tyr2Ter into 155K chip-genotyped Icelanders reveals six additional homozygotes, all with signs of CGD, manifesting as colitis, rare infections, or a severely impaired PMA-induced neutrophil oxidative burst. Homozygosity for p.Tyr2Ter consequently associates with inflammatory bowel disease (IBD) in Iceland (P = 8.3 × 10−8; OR = 67.6), as well as reduced height (P = 3.3 × 10−4; −8.5 cm). Overall, we find that CYBC1 deficiency results in CGD characterized by colitis and a distinct profile of infections indicative of macrophage dysfunction.

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Section: Resultssupporting

confidence: 76%

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease

et al. 2018

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“…Cyba-deficient mice (nmf33 mice) have been shown to develop a CGD-like immune defect, as the inability of the phagocytes to produce bacteria-destroying ROS means that these mice have increased susceptibility to bacterial infections, dying a few days after intratracheal inoculation of Burkholderia cepacia; their lung tissue was greatly damaged by necrotising pneumonia, and the alveolar spaces were filled with neutrophil granulocytes, macrophages, and cell debris, in contrast to only minimal granulocytic infiltration into the peribronchial and perivascular areas in lungs from wild-type mice [25]). In agreement with this, Cyba tm1a mice have been shown to die a few days after intravenous administration of Salmonella enterica serovar Typhimurium [26]. However, this is the first report of the presence of macrophage infiltration in the lungs resulting in the formation of granulomas with eosinophilic crystalline deposits in Cyba-deficient (and Ncf2-deficient) mice that have not been deliberately exposed to a microorganism and that were housed in a specific pathogen-free (SPF) environment.…”

Section: Discussionsupporting

confidence: 59%

Pulmonary metastatic colonisation and granulomas in NOX2‐deficient mice

Weyden

Speak

Swiaţkowska

et al. 2018

The Journal of Pathology

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Metastasis is the leading cause of death in cancer patients, and successful colonisation of a secondary organ by circulating tumour cells (CTCs) is the rate‐limiting step of this process. We used tail‐vein injection of B16‐F10 melanoma cells into mice to mimic the presence of CTCs and to allow for the assessment of host (microenvironmental) factors that regulate pulmonary metastatic colonisation. We found that mice deficient for the individual subunits of the NADPH oxidase of myeloid cells, NOX2 (encoded by Cyba, Cybb, Ncf1, Ncf2, and Ncf4), all showed decreased pulmonary metastatic colonisation. To understand the role of NOX2 in controlling tumour cell survival in the pulmonary microenvironment, we focused on Cyba‐deficient (Cyba tm1a) mice, which showed the most significant decrease in metastatic colonisation. Interestingly, histological assessment of pulmonary metastatic colonisation was not possible in Cyba tm1a mice, owing to the presence of large granulomas composed of galectin‐3 (Mac‐2)‐positive macrophages and eosinophilic deposits; granulomas of variable penetrance and severity were also found in Cyba tm1a mice that were not injected with melanoma cells, and these contributed to their decreased survival. The decreased pulmonary metastatic colonisation of Cyba tm1a mice was not due to any overt defects in vascular permeability, and bone marrow chimaeras confirmed a role for the haematological system in the reduced metastatic colonisation phenotype. Examination of the lymphocyte populations, which are known key regulators of metastatic colonisation, revealed an enhanced proportion of activated T and natural killer cells in the lungs of Cyba tm1a mice, relative to controls. The reduced metastatic colonisation, presence of granulomas and altered immune cell populations observed in Cyba tm1a lungs were mirrored in Ncf2‐deficient (Ncf2 tm1a) mice. Thus, we show that NOX2 deficiency results in both granulomas and the accumulation of antitumoural immune cells in the lungs that probably mediate the decreased pulmonary metastatic colonisation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Eros-/-animals succumb quickly following infection with Salmonella Typhimurium or Listeria Monocytogenes. Eros is highly conserved 3 and has a human orthologue C17ORF62 (hereafter referred to as EROS). We asked whether the gene fulfilled the same function in humans.…”

Section: Resultsmentioning

confidence: 99%

EROS is required for phagocyte NADPH oxidase function in humans and its deficiency causes Chronic Granulomatous Disease

Charbonnier

Schejtman

et al. 2018

Preprint

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The phagocyte respiratory burst is mediated by the phagocyte NADPH oxidase, a multi-protein subunit complex that facilitates production of reactive oxygen species and which is essential for host defence. Monogenic deficiency of individual subunits leads to chronic granulomatous disease (CGD), which is characterized by an inability to make reactive oxygen species, leading to severe opportunistic infections and auto-inflammation. However, not all cases of CGD are due to mutations in previously identified subunits. We recently showed that Eros, a novel and highly conserved ER-resident transmembrane protein, is essential for the phagocyte respiratory burst in mice because it is required for expression of gp91phox-p22phox heterodimer, which are the membrane bound components of the phagocyte NADPH oxidase. We now show that the function of EROS is conserved in human cells and describe a case of CGD secondary to a homozygous EROS mutation that abolishes EROS protein expression. This work demonstrates the fundamental importance of EROS in human immunity and describes a novel cause of CGD.Clinical ImplicationsChronic granulomatous disease is caused by an inability to make reactive oxygen species via the phagocyte NADPH oxidase. Mutations in C17ORF62/EROS, which controls gp91phox- p22phox abundance, are a novel cause of chronic granulomatous disease.Key MessagesThe murine gene, Eros, is known to regulate abundance of gp91phox-p22phox heterodimer and Eros deficient mice are susceptible to infectionWe show that the function of EROS is conserved in human cells and that a homozygous mutation in EROS causes chronic granulomatous disease

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Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity

Abstract: Thomas et al. show that a novel protein, Eros, controls the abundance of components of the phagocyte NADPH oxidase, making it essential for the phagocyte respiratory burst and defense against common infections.

Cited by 57 publications

References 55 publications

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease

A homozygous loss-of-function mutation leading to CYBC1 deficiency causes chronic granulomatous disease

Pulmonary metastatic colonisation and granulomas in NOX2‐deficient mice

EROS is required for phagocyte NADPH oxidase function in humans and its deficiency causes Chronic Granulomatous Disease

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