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 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.

KEYWORDS:

• IL-6
• IL-6R
• STAT3 signaling
• SorLA
• Vps10p domain receptors
• cytokines
• endocytosis

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Articles of Significant Interest Selected from This Issue by the Editors

ACKNOWLEDGMENTS

We thank Hang Pham Jensen, Bodil Basse, and Mitra Shamsali for skilled technical assistance and Peder Madsen for the construction of IL-6RΔtail.

The MIND Center is sponsored by The Lundbeck Foundation.