Cleavage Site Localization Differentially Controls Interleukin-6 Receptor Proteolysis by ADAM10 and ADAM17

被引:76
作者
Riethmueller, Steffen [1 ]
Ehlers, Johanna C. [1 ]
Lokau, Juliane [1 ]
Duesterhoeft, Stefan [1 ]
Knittler, Katharina [1 ]
Dombrowsky, Gregor [1 ]
Groetzinger, Joachim [1 ]
Rabe, Bjoern [1 ]
Rose-John, Stefan [1 ]
Garbers, Christoph [1 ]
机构
[1] Univ Kiel, Inst Biochem, Olshausenstr 40, Kiel, Germany
关键词
NECROSIS-FACTOR-ALPHA; IL-6; RECEPTOR; CYTOKINE; DISINTEGRIN; INHIBITION; EXPRESSION; PROTEASES; PROTEINS; RELEASE; SENESCENCE;
D O I
10.1038/srep25550
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Limited proteolysis of the Interleukin-6 Receptor (IL-6R) leads to the release of the IL-6R ectodomain. Binding of the cytokine IL-6 to the soluble IL-6R (sIL-6R) results in an agonistic IL-6/sIL-6R complex, which activates cells via gp130 irrespective of whether the cells express the IL-6R itself. This signaling pathway has been termed trans-signaling and is thought to mainly account for the pro-inflammatory properties of IL-6. A Disintegrin And Metalloprotease 10 (ADAM10) and ADAM17 are the major proteases that cleave the IL-6R. We have previously shown that deletion of a ten amino acid long stretch within the stalk region including the cleavage site prevents ADAM17-mediated cleavage, whereas the receptor retained its full biological activity. In the present study, we show that deletion of a triple serine (3S) motif (Ser-35(to Ser-361) adjacent to the cleavage site is sufficient to prevent IL-6R cleavage by ADAM17, but not ADAM10. We find that the impaired shedding is caused by the reduced distance between the cleavage site and the plasma membrane. Positioning of the cleavage site in greater distance towards the plasma membrane abrogates ADAM17-mediated shedding and reveals a novel cleavage site of ADAM10. Our findings underline functional differences in IL-6R proteolysis by ADAM10 and ADAM17.
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页数:14
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