Abstract
Interleukin (IL)-11 is a multifunctional cytokine that was traditionally recognized for its hematopoietic and anti-inflammatory functions, but has recently been shown also to be involved in tumorigenesis. IL-11 signaling is initiated by binding of the cytokine to the IL-11 receptor (IL-11R), which is not directly involved in signaling but required for IL-11 binding to the signal-transducing receptor glycoprotein (gp) 130. In classic signaling, IL-11 binds to the membrane-bound IL-11R to initiate signal transduction. Additionally, IL-11 signaling can be initiated via soluble IL-11R, known as trans-signaling, and this pathway only requires the three extracellular domains of the IL-11R, but not stalk, transmembrane, or intracellular region. Here, we analyzed the role of the IL-11R stalk region, a 55 amino acid stretch connecting the extracellular domains with the transmembrane helix, in classic IL-11 signaling with the help of cytokine-dependent cell lines. We showed that the stalk region is crucial for IL-11 signaling via the membrane-bound IL-11R. Using different deletion variants, we found that a minimal length of 23 amino acid residues is required for efficient signal transduction. We further found that classic IL-11 signaling depended solely on the length, but not the sequence, of the IL-11R stalk region, suggesting that the stalk functions as a spacer in the signaling complex. We previously described the IL-11R stalk region as determinant of proteolysis and regulator of IL-11 trans-signaling. The results presented here reveal an additional function in classic IL-11 signaling, highlighting the importance of the IL-11R stalk in IL-11 signaling.
Highlights
Interleukin (IL)-11 is a multifunctional cytokine that was traditionally recognized for its hematopoietic and anti-inflammatory functions, but has recently been shown to be involved in tumorigenesis
We have previously shown that the length of the stalk region of the IL-6R is critical for IL-6 classic signaling [21]
Because the crystal structure of IL-11 suggests differences in the binding of the cytokine to gp130 compared with IL-6, we sought to analyze whether the stalk region of the IL-11 receptor (IL-11R) serves a similar purpose as the stalk of the IL-6 in the correct positioning of the extracellular domains toward gp130, and whether there is a critical length of the stalk region that is needed to allow IL-11 classic signaling
Summary
Induces the Janus kinase/signal transducers and activators of transcription (Jak/STAT) pathway, but has been shown to activate the mitogen-activated protein kinase/extracellular regulated kinase (MAPK/Erk), phosphoinositide 3-kinase (PI3K), and yes-associated protein (YAP) pathways (10 –12). The stalk region is not directly involved in signal transduction, because recombinant soluble IL-11R, which only consists of the three extracellular domains, is able to bind IL-11 and induce signal transduction [17, 18]. It was previously shown that IL-6 classic signaling, which requires a signaling complex that is similar to that of IL-11, depends on an IL-6R stalk region which spans 83.6 Å (22 amino acid residues) [21]. The crystal structure of IL-11 revealed differences from IL-6 in terms of structure and receptor-binding site features, suggesting that IL-11 and IL-6 engage gp130 differently [22] To elucidate these potential differences further, we deleted different stretches of the IL-11R stalk region and analyzed whether and how these deletions influence classic IL-11 signaling. We further show that the signaling capacity depends solely on the length, but not the sequence, of the stalk region
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