The length of the interleukin-11 receptor stalk determines its capacity for classic signaling.

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.

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