The physiological and pathophysiological role of iRhom-2

iRhom-2 的生理和病理生理作用

• 批准号: 221604464
• 负责人: Professor Dr. Philipp Alexander Lang, Ph.D.
• 金额: --
• 依托单位: Institut für Molekulare Medizin II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/221604464?language=en
• 关键词: physiological; pathophysiological; role; iRhom

iRhom2 is a catalytically inactive member of the rhomboid protease family. The involvement of iRhoms in endoplasmic reticulum trafficking has been described. Our new data shows that iRhom2 interacts with the TNF alpha converting enzyme (TACE/ADAM17) regulating its trafficking and activation. Accordingly, iRhom2 triggers inflammation by regulation of TNF alpha secretion. Consistently, iRhom2 deficient mice survive lethal lipopolysaccharide (LPS) injection and succumb to bacterial infection. However the broader role of iRhom2 during infection and autoimmunity remains unclear. The proposed project will analyze the hypothesis that iRhom2 is a central regulator of immune cells, but not of other parenchymal cells. Specifically, the role of iRhom2 on virus infection will be analyzed. During this study, the physiological role of iRhom2 will be characterized, and the involvement of other rhomboid family members on TACE maturation will be investigated. These studies will provide clarification of the differential phenotype observed between the TACE and iRhom2 deficient mice, and further define the nature of the interaction between iRhom2 and TACE. Furthermore, this research project also seeks to investigate an important potential role of iRhom2 in autoimmunity. Taken together, these specific aims will characterize the role of iRhom2 on a molecular and physiologically relevant level. The results of the proposed project will help to evaluate iRhom2 as a potential therapeutic target for TNF alpha induced disease and autoimmunity.

iRhom 2是菱形蛋白酶家族的无催化活性成员。已经描述了iRhoms参与内质网运输。我们的新数据表明，iRhom 2与TNF α转化酶（TACE/ADAM 17）相互作用，调节其运输和激活。因此，iRhom 2通过调节TNF α分泌触发炎症。一致地，iRhom 2缺陷型小鼠在致死性脂多糖（LPS）注射后存活并死于细菌感染。然而，iRhom 2在感染和自身免疫过程中的更广泛作用仍不清楚。拟议的项目将分析iRhom 2是免疫细胞的中央调节器，但不是其他实质细胞的假设。具体而言，将分析iRhom 2对病毒感染的作用。在本研究期间，将表征iRhom 2的生理作用，并将研究其他菱形家族成员对TACE成熟的参与。这些研究将澄清TACE和iRhom 2缺陷小鼠之间观察到的差异表型，并进一步定义iRhom 2和TACE之间相互作用的性质。此外，该研究项目还试图研究iRhom 2在自身免疫中的重要潜在作用。总之，这些特定的目标将在分子和生理相关水平上表征iRhom 2的作用。拟议项目的结果将有助于评估iRhom 2作为TNF α诱导的疾病和自身免疫的潜在治疗靶点。

项目成果

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

• DOI: 10.1073/pnas.1302553110
• 发表时间: 2013-07-09
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Maretzky, Thorsten;McIlwain, David R.;Blobel, Carl P.
• 通讯作者: Blobel, Carl P.

Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+ Macrophage Function during Viral Infection

B 细胞激活因子受体缺陷导致病毒感染期间 CD169 巨噬细胞功能有限

• DOI: 10.1128/jvi.02976-14
• 发表时间: 2015
• 期刊: Journal of Virology
• 影响因子: 5.4
• 作者: Huang J;Khairnar V;Duhan V;Pandyra AA;Grusdat M;Shinde P;McIlwain DR;Maney SK;Gommerman J;Löhning M;Ohashi PS;Mak TW;Pieper K;Speletas M;Eibel H;Ware CF;Tumanov AV;Kruglov AA;Nedospasov SA;Häusinger D;Recher M;Lang KS
• 通讯作者: Lang KS