SorLA in Interleukin-6 Signaling and Turnover

• Published in: Molecular and cellular biology Vol. 37; no. 11
• Main Authors: Larsen, Jakob Vejby, Petersen, Claus Munck
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.06.2017; American Society for Microbiology
• 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; IL-6R; Vps10p domain receptors; STAT3 signaling; endocytosis; cytokines; IL-6; SorLA
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00641-16

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.