Mammalian iRhoms have distinct physiological functions including an essential role in TACE regulation.
Mammalian iRhoms have distinct physiological functions including an essential role in TACE regulation.
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DOI：
10.1038/embor.2013.128
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发表时间：
2013-10
期刊：
影响因子：
7.7
通讯作者：
Freeman, Matthew
中科院分区：
文献类型：
--
作者：
Christova, Yonka;Adrain, Colin;Bambrough, Paul;Ibrahim, Ashraf;Freeman, Matthew
iRhom 2是一种无催化活性的菱形样蛋白，其缺失可阻断巨噬细胞中TACE/ADAM 17的成熟，导致细胞因子TNF的脱落缺陷。除了产生的炎症缺陷，iRhom 2缺失小鼠表现正常：它们没有表现出在TACE敲除中观察到的多重缺陷，表明TACE成熟不依赖于巨噬细胞以外的细胞中的iRhom 2。在这里，我们表明，iRhoms的生理作用要广泛得多。iRhom 1基因敲除小鼠在出生后6周内死亡。它们表现出严重的表型，在多个组织中存在缺陷，包括高度渗透性脑出血。非重叠表型意味着iRhom 1和2具有不同的生理作用，尽管在细胞水平上都促进TACE的成熟（但不是其他ADAM蛋白酶）。两种iRhom在TACE起作用的许多情况下共同表达。我们得出结论，所有TACE活性，组成和调节，需要iRhom功能。因此，iRhoms是TACE活性的重要和特定调节剂，但我们的证据也表明它们必须有其他生理上重要的客户。
Loss of iRhom2, a catalytically inactive rhomboid-like protein, blocks maturation of TACE/ADAM17 in macrophages, resulting in defective shedding of the cytokine TNF. Apart from the resulting inflammatory defects, iRhom2-null mice appear normal: they do not exhibit the multiple defects seen in TACE knockouts, suggesting that TACE maturation is independent of iRhom2 in cells other than macrophages. Here we show that the physiological role of iRhoms is much broader. iRhom1 knockout mice die within 6 weeks of birth. They exhibit a severe phenotype, with defects in multiple tissues including highly penetrant brain haemorrhages. The non-overlapping phenotypes imply that iRhom 1 and 2 have distinct physiological roles, although at a cellular level both promote the maturation of TACE (but not other ADAM proteases). Both iRhoms are co-expressed in many contexts where TACE acts. We conclude that all TACE activity, constitutive and regulated, requires iRhom function. iRhoms are therefore essential and specific regulators of TACE activity, but our evidence also implies that they must have additional physiologically important clients.
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影响因子：
64.5
作者：
Zettl M;Adrain C;Strisovsky K;Lastun V;Freeman M
通讯作者：
Freeman M
影响因子：
2.2
作者：
Saarinen, Silva;Vahteristo, Pia;Aaltonen, Lauri A.
通讯作者：
Aaltonen, Lauri A.
DOI：
10.3109/10409231003628015
发表时间：
2010-04
影响因子：
6.5
作者：
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通讯作者：
Gooz M
影响因子：
4.1
作者：
Schlöndorff, J;Becherer, JD;Blobel, CP
通讯作者：
Blobel, CP
影响因子：
4.8
作者：
Zou, Huafei;Thomas, Sufi M.;Li, Lu-Yuan
通讯作者：
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