A soluble form of the interleukin-6 family signal transducer gp130 is dimerized via a C-terminal disulfide bridge resulting from alternative mRNA splicing

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• 作者：Janina Wolf^a ; Georg H. Waetzig^b ; Torsten M. Reinheimer^c ; Jü ; rgen Scheller^d ; Stefan Rose-John^a ; Christoph Garbers^a ; ^{cgarbers@biochem.uni-kiel.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Interleukin-6 ; IL-6R ; Gp130 ; Sgp130 ; Trans-signaling
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2016
• 出版时间：19 February 2016
• 年：2016
• 卷：470
• 期：4
• 页码：870-876
• 全文大小：941 K

文摘

Interleukin-6 (IL-6) signaling can be divided into classic signaling (via the membrane-bound IL-6 receptor, IL-6R) and trans-signaling (via the soluble IL-6R, sIL-6R), and both modes of signaling activate cells via a homodimer of the ubiquitously expressed β-receptor glycoprotein 130 (gp130). IL-6 trans-signaling is responsible for most of the pro-inflammatory activities of IL-6 and plays a role in many inflammatory diseases including inflammation-driven cancers. IL-6 trans-signaling can be selectively inhibited by soluble forms of gp130. To date, three forms of sgp130 (full-length sgp130, sgp130-RAPS and sgp130-E10) with different molecular weight have been described, which originate from alternative splicing or alternative polyadenylation of the gp130 mRNA. All these proteins are capable of blocking signaling of the IL-6/sIL-6R complex, albeit with different efficacy. The full length form of sgp130 comprises the domains D1 to D6 and a short unique C-terminus which arises from alternative splicing. In the present study, we analyze the role of a unique cysteine residue (Cys-628) within this C-terminus, which is contained neither in the membrane-bound gp130 nor in the two other sgp130 forms. Full-length sgp130 can form a disulfide-linked dimer via this cysteine residue. These natural sgp130 dimers are absent under reducing conditions or in a sgp130 C628A mutant. Although the disulfide-dimerized sgp130 represents only a small fraction of the total amount of sgp130 and, thus, may appear to be dispensable for the global inhibitory activities of sgp130 in the circulation, it may represent a further possibility to modulate gradients of sgp130 with different properties depending on the local redox potential in a cell- or tissue-dependent manner.