A Di-leucine Motif and an Upstream Serine in the Interleukin-6 (IL-6) Signal Transducer gp130 Mediate Ligand-induced Endocytosis and Down-regulation of the IL-6 Receptor
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The interleukin-6 (IL-6) receptor complex is composed of two different subunits, the IL-6 binding protein (IL-6R, gp80) and the signal transducing component gp130. Our previous studies revealed that the 10-amino acid sequence TQPLLDSEER within the intracellular domain of gp130 is crucial for the efficient internalization of IL-6. Since this sequence contains a putative di-leucine internalization motif, we further analyzed this region by constructing two additional deletions and a series of point mutants. Analyses of these mutants showed that the di-leucine pair (Leu-145 and Leu-146) is essential for ligand internalization, with leucine 145 being less resilient to exchanges. Furthermore, when a chimeric protein (Tac-STQPLL) composed of the Tac antigen fused to the hexapeptide STQPLL of gp130 was studied, we found that this sequence is sufficient to mediate endocytosis and lysosomal targeting of the chimera. Mutational analysis of three serine residues upstream of the di-leucine motif revealed that mutation of serine 139 to an alanine reduces the initial internalization rate by 50%. This finding suggests that a serine phosphorylation may be important for rapid endocytosis.
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The cytoplasmic domain of LRAD3 contains a conserved dileucine motif.
“Instead, the cytoplasmic domain of LRAD3 contains a conserved dileucine motif which has been demonstrated to mediate endocytosis and sorting of many receptors, including CD3 (Letourneur and Klausner, 1992), IgG Fc receptors (Hunziker and Fumey, 1994), the IL-6 receptor (Dittrich et al., 1996), and CD44 (Sheikh and Isacke, 1996).”
From LRAD3, A Novel Low-Density Lipoprotein Receptor Family Member That Modulates Amyloid Precursor Protein Trafficking (2011) · cites this paper as Dittrich et al., 1996
The dileucine motif mediates endocytosis and sorting of many receptors.
“the cytoplasmic domain of LRAD3 contains a conserved dileucine motif which has been demonstrated to mediate endocytosis and sorting of many receptors, including CD3 (Letourneur and Klausner, 1992), IgG Fc receptors (Hunziker and Fumey, 1994), the IL-6 receptor (Dittrich et al., 1996), and CD44 (Sheikh and Isacke, 1996).”
From LRAD3, A Novel Low-Density Lipoprotein Receptor Family Member That Modulates Amyloid Precursor Protein Trafficking (2011) · cites this paper as Dittrich et al., 1996
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- Authors
- Dittrich, E., Haft, C. R., Muys, L., Heinrich, P. C., & Graeve, L.
- Affiliations
- RWTH Aachen University (DE)
- National Institutes of Health (US)
- Corresponding author
- Graeve, Lutz
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1996-03
- Volume
- 271
- Issue
- 10
- Pages
- 5487-5494
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2016409733
- Cited by
- 160
- References
- 50
- Citations by year
- 2025: 2 · 2023: 3 · 2021: 3 · 2020: 2 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 8 · 2014: 4 · 2013: 2 · 2012: 4
- FWCI
- 7.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- IL-6 receptor, gp130, dileucine motif, endocytosis, receptor down-regulation, serine phosphorylation, ligand internalization, lysosomal targeting, point mutations, cytoplasmic domain
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Binding Sites, Cell Line, Cell Membrane, Chlorocebus aethiops, DNA Mutational Analysis, Endocytosis, Humans, Kinetics, Leucine, Ligands, Lysosomes, Membrane Glycoproteins, Molecular Sequence Data, Oligodeoxyribonucleotides, Phosphorylation, Recombinant Proteins, Serine, Time Factors, Transfection, Signal Transduction, Down-Regulation, Antigens, CD, Interleukin-6, Mutagenesis, Mutagenesis, Site-Directed, Point Mutation, Sequence Deletion, Receptors, Interleukin, Receptors, Interleukin-6, Cytokine Receptor gp130
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