Abstract
The cytokine Interleukin-11 (IL-11) signals through the membrane-bound IL-11 receptor (IL-11R), which is expressed in a cell-type specific manner. We have recently shown that the metalloprotease ADAM10 can cleave the IL-11R. The liberated soluble IL-11R (sIL-11R) ectodomain can bind its ligand, and the resulting IL-11/sIL-11R complex can activate cells that do not express the IL-11R (trans-signaling). In this study, we show that the remaining C-terminal fragment (CTF1) after ADAM10-mediated cleavage is subsequently cleaved within the membrane by the gamma-secretase complex, and that the resulting shorter CTF2 is further degraded by the proteasome. In contrast to other transmembrane receptors, e.g. Notch, we find no evidence that the IL-11R CTF can translocate into the nucleus to act as a transcription factor, suggesting that regulated intramembrane proteolysis of the IL-11R CTF acts as a mechanism to clear the plasma membrane from remaining protein fragments after cleavage of its ectodomain.
Keywords:
Gamma-secretase; Interleukin-11; Interleukin-11 receptor; Proteasome; Proteolysis.
Copyright © 2017 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM10 Protein / genetics
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ADAM10 Protein / immunology
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ADAM10 Protein / metabolism*
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / immunology
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Amyloid Precursor Protein Secretases / metabolism*
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Animals
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Cell Line, Tumor
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Cell Membrane / immunology
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Cell Membrane / metabolism
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Gene Expression
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Interleukin-11 / genetics
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Interleukin-11 / immunology
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Interleukin-11 / metabolism*
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Ligands
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism*
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Mice
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Peptide Fragments / genetics
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Peptide Fragments / immunology
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Peptide Fragments / metabolism
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Precursor Cells, B-Lymphoid / cytology
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Precursor Cells, B-Lymphoid / immunology
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Precursor Cells, B-Lymphoid / metabolism*
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Proteasome Endopeptidase Complex / metabolism*
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Protein Binding
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Proteolysis
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Receptors, Interleukin-11 / genetics
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Receptors, Interleukin-11 / immunology
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Receptors, Interleukin-11 / metabolism*
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Signal Transduction
Substances
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Interleukin-11
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Ligands
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Membrane Proteins
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Peptide Fragments
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Receptors, Interleukin-11
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Amyloid Precursor Protein Secretases
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ADAM10 Protein
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Adam10 protein, mouse
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Proteasome Endopeptidase Complex