iRhom2 Regulation of TACE Controls TNF-Mediated Protection Against
            <i>Listeria</i>
            and Responses to LPS

McIlwain, David R.; Lang, Philipp A.; Maretzky, Thorsten; Hamada, Koichi; Ohishi, Kazuhito; Maney, Sathish Kumar; Berger, Thorsten; Murthy, Aditya; Duncan, Gordon S.; Xu, Haifeng; Lang, Karl S.; Häussinger, Dieter; Wakeham, Andrew; Itie-YouTen, Annick; Khokha, Rama; Ohashi, Pamela S.; Blobel, Carl P.; Mak, Tak W.

doi:10.1126/science.1214448

Cited by 302 publications

(446 citation statements)

References 34 publications

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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%

iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding

Maretzky

McIlwain

Issuree

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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148

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Protein ectodomain shedding by ADAM17 (a disintegrin and metalloprotease 17), a principal regulator of EGF-receptor signaling and TNFα release, is rapidly and posttranslationally activated by a variety of signaling pathways, and yet little is known about the underlying mechanism. Here, we report that inactive rhomboid protein 2 (iRhom2), recently identified as essential for the maturation of ADAM17 in hematopoietic cells, is crucial for the rapid activation of the shedding of some, but not all substrates of ADAM17. Mature ADAM17 is present in mouse embryonic fibroblasts (mEFs) lacking iRhom2, and yet ADAM17 is unable to support stimulated shedding of several of its substrates, including heparin-binding EGF and Kit ligand 2 in this context. Stimulated shedding of other ADAM17 substrates, such as TGFα, is not affected in iRhom2 −/− mEFs but can be strongly reduced by treating iRhom2 −/− mEFs with siRNA against iRhom1. Activation of heparin-binding EGF or Kit ligand 2 shedding by ADAM17 in iRhom2 −/− mEFs can be rescued by wild-type iRhom2 but not by iRhom2 lacking its N-terminal cytoplasmic domain. The requirement for the cytoplasmic domain of iRhom2 for stimulated shedding by ADAM17 may help explain why the cytoplasmic domain of ADAM17 is not required for stimulated shedding. The functional relevance of iRhom2 in regulating shedding of EGF receptor (EGFR) ligands is established by a lack of lysophasphatidic acid/ADAM17/ EGFR-dependent crosstalk with ERK1/2 in iRhom2 −/− mEFs, and a significant reduction of FGF7/ADAM17/EGFR-stimulated migration of iRhom2 −/− keratinocytes. Taken together, these findings uncover functions for iRhom2 in the regulation of EGFR signaling and in controlling the activation and substrate selectivity of ADAM17-dependent shedding events.

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mentioning

confidence: 99%

iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding

Maretzky

McIlwain

Issuree

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

148

223

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“…Mechanistically, Rhbdd3 localizes in early endosomes in DCs and interacts with K27-linked ubiquitination of NF-κB essential modifier (NEMO) and subsequently recruits A20 to facilitate A20-mediated K63-linked deubiquitination of NEMO. 72,73 By contrast, iRhom2, a novel noncatalytic relative of rhomboid proteins, facilitates LPS and Listeria-induced TNF production by promoting the TNF convertase (TACE) maturation and trafficking, 74,75 and also enhances innate immunity to DNA viruses by mediating STING trafficking and stability. 76 The differential regulation of innate immunity by Rhomboid family members awaits further investigation, and is likely to be related with their different subcellular localization that may provide specific biochemical and physical environment for specific signaling modifications.…”

Section: Molecular Regulation Of Innate Immunity and Inflammationmentioning

confidence: 99%

Cellular and molecular regulation of innate inflammatory responses

2016

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“…Similar to ADAM17 KO mice, mice deficient for iRhom2 are defective in TNF release from myeloid cells. iRhom2 KO mice respond less severely to sepsis, are protected from experimental arthritis, but exhibit increased sensitivity to Listeria infection, hallmarks of TNF biology [12, [22][23][24]. iRhom redundancy is illustrated by the fact that iRhom single KO mouse embryonic fibroblasts retain substantial ADAM17 activity, whereas ADAM17 is inactive in double knockout (DKO) cells [20,21].…”

Section: Pseudoprotease Function In Growth Factor Signaling and Inflamentioning

confidence: 99%

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Lemberg

Adrain

2016

Seminars in Cell & Developmental Biology

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Rhomboids, proteases containing an unusual membrane-integral serine protease active site, were first identified in Drosophila, where they fulfill an essential role in epidermal growth factor receptor signaling, by cleaving membrane-tethered growth factor precursors. It has recently become apparent that eukaryotic genomes harbor conserved catalytically inactive rhomboid protease homologs, including derlins and iRhoms. Here we highlight how loss of proteolytic activity was followed in evolution by impressive functional diversification, enabling these pseudoproteases to fulfill crucial roles within the secretory pathway, including protein degradation, trafficking regulation, and inflammatory signaling. We distil the current understanding of the roles of rhomboid pseudoproteases in development and disease.

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iRhom2 Regulation of TACE Controls TNF-Mediated Protection Against Listeria and Responses to LPS

Cited by 302 publications

References 34 publications

iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding

iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding

Cellular and molecular regulation of innate inflammatory responses

Inactive rhomboid proteins: New mechanisms with implications in health and disease

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