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Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.

ABSTRACT: The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, ADAM17 (TNF?-converting enzyme, TACE). We report that iRhom2 (RHBDF2), a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes its exit from the endoplasmic reticulum. The failure of TACE to exit the endoplasmic reticulum in the absence of iRhom2 prevents the furin-mediated maturation and trafficking of TACE to the cell surface, the site of TNF cleavage. Given the role of TNF in autoimmune and inflammatory diseases, iRhom2 may represent an attractive therapeutic target.

SUBMITTER: Adrain C

PROVIDER: S-EPMC3272371 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.

Adrain Colin C Zettl Markus M Christova Yonka Y Taylor Neil N Freeman Matthew M

Science (New York, N.Y.) 20120101 6065

The cytokine tumor necrosis factor (TNF) is the primary trigger of inflammation. Like many extracellular signaling proteins, TNF is synthesized as a transmembrane protein; the active signal is its ectodomain, which is shed from cells after cleavage by an ADAM family metalloprotease, ADAM17 (TNFα-converting enzyme, TACE). We report that iRhom2 (RHBDF2), a proteolytically inactive member of the rhomboid family, is required for TNF release in mice. iRhom2 binds TACE and promotes its exit from the e ...[more]

PMID: 22246777

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Project description:Preeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy for which the pathophysiology remains largely undefined. Recently, a circulating maternal autoantibody, the angiotensin II type I (AT(1)) receptor agonistic autoantibody (AA), has emerged as a contributor to disease features. Increased circulating maternal tumor necrosis factor alpha (TNF-alpha) is also associated with the disease; however, it is unknown whether this factor directly contributes to preeclamptic symptoms. Here we report that this autoantibody increases the proinflammatory cytokine TNF-alpha in the circulation of AT(1)-AA-injected pregnant mice but not in nonpregnant mice. Coinjection of AT(1)-AA with a TNF-alpha neutralizing antibody reduced cytokine availability in AT(1)-AA-injected pregnant mice. Moreover, TNF-alpha blockade in AT(1)-AA-injected pregnant mice significantly attenuated the key features of preeclampsia. Autoantibody-induced hypertension was reduced from 131+/-4 to 110+/-4 mm Hg, and proteinuria was reduced from 212+/-25 to 155+/-23 microg of albumin per milligram of creatinine (both P<0.05). Injection of AT(1)-AA increased the serum levels of circulating soluble fms-like tyrosine kinase 1 and soluble endoglin (34.1+/-5.1, 2.4+/-0.3 ng/mL, respectively) and coinjection with the TNF-alpha blocker significantly reduced their levels (21.7+/-3.4 and 1.2+/-0.4 ng/mL, respectively). Renal damage and placental abnormalities were also decreased by TNF-alpha blockade. Lastly, the elevated circulating TNF-alpha in preeclamptic patients is significantly correlated with the AT(1)-AA bioactivity in our patient cohort. Similarly, the autoantibody, through AT(1) receptor-mediated TNF-alpha induction, contributed to increased soluble fms-like tyrosine kinase 1, soluble endoglin secretion, and increased apoptosis in cultured human villous explants. Overall, AT(1)-AA is a novel candidate that induces TNF-alpha, a cytokine that may play an important pathogenic role in preeclampsia.

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Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.

Publications

Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE.

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