SorLA in Interleukin-6 Signaling and Turnover

Interleukin-6 (IL-6) is a multifunctional cytokine with important functions in various physiologic processes. Mice lacking IL-6 exhibit multiple phenotypic abnormalities, such as an inadequate immune and acute-phase response, and elevated levels of circulating IL-6 have been found to accompany sever...

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Bibliographic Details
Published in:Molecular and cellular biology 2017-06, Vol.37 (11)
Main Authors: Larsen, Jakob Vejby, Petersen, Claus Munck
Format: Article
Language:English
Subjects:
Animals
Astrocytes - metabolism
Cell Membrane - metabolism
cytokines
Down-Regulation
Endocytosis
Half-Life
HEK293 Cells
Humans
IL-6
IL-6R
Interleukin-6 - metabolism
LDL-Receptor Related Proteins - metabolism
Membrane Transport Proteins - metabolism
Mice, Knockout
Peptides - metabolism
Protein Binding
Protein Domains
Protein Stability
Receptors, Interleukin-6 - chemistry
Receptors, Interleukin-6 - metabolism
Receptors, LDL - metabolism
Signal Transduction
Solubility
SorLA
Spotlight
STAT3 signaling
Transfection
Vps10p domain receptors
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Summary:Interleukin-6 (IL-6) is a multifunctional cytokine with important functions in various physiologic processes. Mice lacking IL-6 exhibit multiple phenotypic abnormalities, such as an inadequate immune and acute-phase response, and elevated levels of circulating IL-6 have been found to accompany several pathological conditions. IL-6 binds the nonsignaling IL-6 receptor (IL-6R), which is expressed as a transmembrane, as well as a secreted circulating protein, before it engages homodimeric gp130 for signaling. Complex formation between IL-6 and the membrane-bound IL-6 receptor gives rise to classic cis signaling, whereas complex formation between IL-6 and the soluble IL-6R results in trans signaling. Here, we report that the endocytic receptor SorLA targets IL-6 and IL-6R. We present evidence that SorLA mediates efficient cellular uptake of both IL-6 and the circulating IL-6R in astrocytes. We further show that SorLA interacts with the membrane-bound IL-6R at the cell surface and thereby downregulates IL-6 cis signaling. Finally, we find that the SorLA ectodomain, released from the cell membrane upon enzymatic cleavage of full-length SorLA, may act as an IL-6 carrier protein that stabilizes IL-6 and its capacity for trans signaling.
ISSN:1098-5549
0270-7306
1098-5549
DOI:10.1128/MCB.00641-16