Publication Date:
2012-01-17
Description:
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 (TNFalpha-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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272371/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272371/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adrain, Colin -- Zettl, Markus -- Christova, Yonka -- Taylor, Neil -- Freeman, Matthew -- MC_U105178780/Medical Research Council/United Kingdom -- U.1051.01.009(78780)/Medical Research Council/United Kingdom -- U105178780/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2012 Jan 13;335(6065):225-8. doi: 10.1126/science.1214400.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22246777" target="_blank"〉PubMed〈/a〉
Keywords:
ADAM Proteins/*metabolism
;
Animals
;
Carrier Proteins/genetics/*metabolism
;
Cell Line
;
Cell Membrane/metabolism
;
Endoplasmic Reticulum/metabolism
;
Enzyme Activation
;
Furin/metabolism
;
Humans
;
Lipopolysaccharides/immunology
;
Macrophages/metabolism
;
Mice
;
Mice, Knockout
;
Protein Binding
;
Protein Transport
;
*Signal Transduction
;
Tumor Necrosis Factor-alpha/*metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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