2012
DOI: 10.1182/blood-2012-03-417949
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iRhom2 is required for the secretion of mouse TNFα

Abstract: TNF␣ is a powerful inflammatory stimulus, central both to the control of infection, and as an agent of inflammatory disease. The most potent inducers of TNF␣ secretion signal through the Toll-like receptors, and we describe here a chemically-induced mutation that impairs this response in macrophages. A missense mutation was revealed in the gene encoding the inactive rhomboid protease iRhom2, which was not complemented by a null allele of the same gene. Neither the missense nor the null allele affected TLR-indu… Show more

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Cited by 87 publications
(114 citation statements)
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References 22 publications
(23 reference statements)
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“…These findings raise the possibility that other transmembrane proteins that interact with ADAM17 could have a role in activation of ADAM17-dependent shedding. Recently, the inactive Rhomboid iRhom2, a catalytically inactive member of the Rhomboid family of intramembrane proteinases (19)(20)(21)(22), was identified as a crucial regulator of the maturation of ADAM17 in hematopoietic cells. Interestingly, mature ADAM17 is present in several tissues and cell types of iRhom2 −/− mice, including mouse embryonic fibroblasts (mEFs) and keratinocytes (7,23).…”
mentioning
confidence: 99%
“…These findings raise the possibility that other transmembrane proteins that interact with ADAM17 could have a role in activation of ADAM17-dependent shedding. Recently, the inactive Rhomboid iRhom2, a catalytically inactive member of the Rhomboid family of intramembrane proteinases (19)(20)(21)(22), was identified as a crucial regulator of the maturation of ADAM17 in hematopoietic cells. Interestingly, mature ADAM17 is present in several tissues and cell types of iRhom2 −/− mice, including mouse embryonic fibroblasts (mEFs) and keratinocytes (7,23).…”
mentioning
confidence: 99%
“…Myeloid cells lacking iRhom2 release very little TNF-α in response to activation of Toll-like receptor 4 by lipopolysaccharide (LPS) (24,26,28). Therefore, mice lacking iRhom2 are protected from the detrimental effects of TNF-α in mouse models for septic shock and inflammatory arthritis, similar to conditional knockout mice lacking ADAM17 in myeloid cells (11,26,29).…”
mentioning
confidence: 77%
“…2H), demonstrating that the functions of ADAM17 in microglia and circulating leukocytes depend on iRhom2 and not iRhom1. The normal appearance and behavior of iR1 −/− mice (this study) or iR2 −/− mice (24,26,28) and the finding that treatment of iR2 −/− mEFs with iRhom1 siRNA reduced the function of ADAM17 (27,29) led us to examine possible compensatory or redundant roles of iRhoms 1 and 2 during mouse development by simultaneously inactivating both iRhoms. Matings of iR1 +/− iR2 −/− mice yielded iR1/2 −/− double knockout offspring at the expected Mendelian ratio (Fig.…”
Section: Resultsmentioning
confidence: 99%
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“…Recently, the inactive rhomboid-like proteins Rhbdf1 and Rhbdf2, which have seven-membrane-spanning domains, have emerged as key regulators of ADAM17 (Adrain et al, 2012;Christova et al, 2013;Li et al, 2015;Maretzky et al, 2013;McIlwain et al, 2012;Siggs et al, 2012). Rhbdf2 is crucial for the maturation and function of ADAM17 in myeloid cells, and therefore mice lacking Rhbdf2 are protected from ADAM17-and TNFα-dependent septic shock and inflammatory arthritis McIlwain et al, 2012).…”
Section: Introductionmentioning
confidence: 99%