title: SorLA in Interleukin-6 Signaling and Turnover.
abstract: 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 classiccissignaling, whereas complex formation between IL-6 and the soluble IL-6R results intranssignaling. 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-6cissignaling. 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 fortranssignaling.
authors.affiliation: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark jvl@biomed.au.dk cmp@biomed.au.dk.
authors.forename: Jakob Vejby
authors.initials: JV
authors.lastname: Larsen
authors.affiliation: The MIND Center, Department of Biomedicine, Aarhus University, Aarhus, Denmark jvl@biomed.au.dk cmp@biomed.au.dk.
authors.forename: Claus Munck
authors.initials: CM
authors.lastname: Petersen
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D018345:Mice, Knockout; D010455:Peptides / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains; D055550:Protein Stability; D019947:Receptors, Interleukin-6 / Q000737:chemistry / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D015398:Signal Transduction; D012995:Solubility; D014162:Transfection
chemical_list: D015850:Interleukin-6; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D010455:Peptides; D019947:Receptors, Interleukin-6; D011973:Receptors, LDL; C102582:SORL1 protein, human; C491168:Sorl1 protein, mouse
keywords: IL-6; IL-6R; STAT3 signaling; SorLA; Vps10p domain receptors; cytokines; endocytosis