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Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease [T cells]

ABSTRACT: Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease [T cells]

PROVIDER: PRJNA766691 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16091400_1.fastq.gz	Fastqsanger.gz
	SRR16091400_2.fastq.gz	Fastqsanger.gz
	SRR16091401_1.fastq.gz	Fastqsanger.gz
	SRR16091401_2.fastq.gz	Fastqsanger.gz
	SRR16091402_1.fastq.gz	Fastqsanger.gz

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Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease

Project description:Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease

| PRJNA766689 | ENA

Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease [whole blood]

Project description:Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease [whole blood]

| PRJNA766692 | ENA

Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease [T cells]

Project description:We report a pleiotropic disease due to loss-of-function mutations in RHBDF2, the gene encoding iRHOM2, in 2 kindreds with recurrent infections in different organs. One patient had recurrent pneumonia but no colon involvement, another had recurrent infectious hemorrhagic colitis but no lung involvement, and the other two experienced recurrent respiratory infections. Loss of iRHOM2, a rhomboid superfamily member that regulates the ADAM17 metalloproteinase, caused defective ADAM17-dependent cleavage and release of cytokines, including TNF and amphiregulin. To understand the diverse clinical phenotypes, we challenged Rhbdf2-/- mice with Pseudomonas aeruginosa by nasal gavage and observed more severe pneumonia whereas infection with Citrobacter rodentium caused worse inflammatory colitis than wild-type mice. The fecal microbiota in the colitis patient had characteristic oral species that can predispose to colitis. Thus, a new human immunodeficiency arising from iRHOM2 deficiency causes divergent disease phenotypes that can involve the local microbial environment.

2021-11-03 | GSE184875 | GEO

Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease [whole blood]

2021-11-03 | GSE184876 | GEO

iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

Project description:iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

| PRJNA741289 | ENA

iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

Project description:iRHOM2 deficiency causes environmentally directed immunodysregulatory disease

| PRJNA741290 | ENA

Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-11-03 | GSE184877 | GEO

iRhom2 Promotes Lupus Nephritis through ADAM17-Dependent TNF-α and EGFR Signaling

Project description:Lupus nephritis (LN) often results in progressive renal dysfunction. The inactive Rhomboid 2 (iRhom2) is a newly identified key regulator of A disintegrin and metalloprotease 17 (ADAM17), whose substrates, such as TNF-α and heparin-binding EGF (HB-EGF), have been implicated in the pathogenesis of chronic kidney disease. Here we demonstrate that deficiency of iRhom2 protects the lupus-prone Fcgr2b-/- mice from developing severe kidney damage without altering anti-double stranded (ds) DNA Ab production, by simultaneously blocking the HB-EGF/EGFR and the TNF-α signaling in the kidney tissues. Unbiased transcriptome profiling of kidneys and kidney macrophages revealed that TNF-α and HB-EGF/EGFR signaling pathways are highly upregulated in Fcgr2b-/- mice; alterations that were diminished in the absence of iRhom2. Pharmacological blockade of either TNF-α or EGFR signaling protected Fcgr2b-/- mice from severe renal damage. Finally, kidneys from LN patients showed increased iRhom2 and HB-EGF expression, with interstitial HB-EGF expression significantly associated with chronicity indices. Our data suggest that activation of iRhom2/ADAM17-dependent TNF-α and EGFR signaling plays a crucial role in mediating irreversible kidney damage in LN, thereby uncovering a novel target for selective and simultaneous dual inhibition of two major pathological pathways in the effector arm of the disease.

2019-01-01 | GSE107705 | GEO

Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-dependent Adaptation

Project description:The cell surface metalloprotease ADAM17 and its binding partners iRhom2 and iRhom1 modulate cell-cell interactions by mediating the release of membrane proteins such as TNFa and EGFR-ligands from the cell surface. Most cell types express both iRhoms, though myeloid cells exclusively express iRhom2, and iRhom1 is the main iRhom in the mouse brain. Here we report that iRhom2 is uniquely expressed in olfactory sensory neurons (OSNs), highly specialized cells expressing one olfactory receptor (OR) from a repertoire of over a thousand OR genes in mice. iRhom2-/- mice had no evident morphological defects in the olfactory epithelium (OE), yet RNAseq analysis revealed differential expression of a small subset of ORs. Notably, while the majority of ORs remain unaffected in iRhom2-/- OE, OSNs expressing ORs that are enriched in iRhom2-/- OE showed fewer gene expression changes upon odor environmental changes than the majority of OSNs. Moreover, we discovered an inverse correlation between the expression of iRhom2 compared to OSN activity genes and that odor exposure negatively regulates iRhom2 expression. Given that ORs are specialized G-protein coupled receptors (GPCRs) and many GPCRs activate iRhom2/ADAM17, we investigated if ORs could activate iRhom2/ADAM17. Activation of OR2AT4 by its agonist sandalore in keratinocytes, where this receptor is ectopically expressed, leads to ERK1/2 phosphorylation, likely via an iRhom2/ADAM17-dependent pathway. Taken together, these findings point to a mechanism by which odor stimulation of OSNs activates iRhom2/ADAM17 catalytic activity, resulting in downstream transcriptional changes to the OR repertoire and activity genes, and driving a negative feedback loop to downregulate iRhom2 expression.

2024-05-28 | GSE268171 | GEO

The human iRHOM2 interactome upon KRAS expression

Project description:ADAM17 is a cell surface protease that controls the release of the ectodomains of signalling proteins including EGFR ligands and the primary inflammatory cytokine TNF. Reflecting this important role in signalling, dysregulated ADAM17 activity is linked to many human diseases including immunodeficiency, inflammatory bowel disease (IBD), rheumatic arthritis, cancer, and Alzheimer’s disease. iRhom2, a pseudoprotease of the rhomboid-like superfamily, has evolved to be a multifunctional regulatory co-factor of ADAM17. Recent structural and functional work has begun to reveal how the iRhom2 transmembrane and extracellular domains act to control ADAM17 activity. The cytoplasmic domain, however, remains less explored. Here, using a combination of proteomic, genetic and biochemical approaches, we report three distinct mechanisms by which the cytoplasmic domain of iRhom2 contributes to ADAM17 regulation. First, upon oncogenic KRAS signalling, the serine/threonine kinase RSK2 is recruited to the iRhom2 cytoplasmic N-terminus, and coordinates with phosphorylated ERK to mediate the activation of ADAM17. Second, we show that iRhom2 may have an inhibitory function on ADAM17 at the cell surface: stabilising iRhom2 at cell surface by overexpressing iRhom2’s cytoplasmic binding partner, FRMD8, inhibits PMA-stimulated ADAM17 activity. Third, we have identified a previously undefined motif (RKR) in the iRhom2 cytoplasmic domain that represses unstimulated ADAM17 activity. Overall, these findings reveal the complex regulatory system by which the iRhom2 cytoplasmic tail transduces cellular signals to regulate ADAM17 activation, potentially paving the way towards understanding and possibly manipulating the iRhom2/ADAM17 complex in health and disease.

2025-10-20 | PXD063983 | Pride

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