IL-6 Family Receptor Review

IL-6 family receptors are receptors for IL-6 family ligands, including IL-6R/CD126, gp130/IL6ST, ciliary neurotrophic factor receptor (CNTFR) oncostatin M receptor and leukemia inhibitory factor receptor (LIFR). These cytokines function by binding to its receptor complex, which share the same subunit gp130 (this can be shown in the below picture). That's the reason why these cytokines are referred to as IL-6 family.

The following will briefly introduce structures and functions of the IL-6 receptor complex and other IL-6 family receptors.

IL-6 family receptor complex

The IL-6 Receptor Complex

The fully competent IL-6R is composed of an 80-kilodalton type 1 cytokine a-receptor subunit (IL-6R; also known as CD126), which binds IL-6, and a universally expressed 130-kilodalton signal-transducing β-receptor subunit (gp130; also known as CD130; encoded by IL6ST).

Structure-function studies predict that a functioning IL-6 receptor requires the formation of an IL-6–IL-6R–gp130 complex that is clustered into a dimer structure.

The IL-6R is a glycosylated type I membrane 80 kDa protein. The Ig-like domain of the human IL-6R is not required for binding of IL-6 but stabilizes the receptor during intracellular trafficking through the secretory pathway. Binding of IL-6 to IL-6R is mediated by residues on domains 2 and 3 of the IL-6R. Interestingly, murine IL-6R lacking the Ig-domain was not able to bind IL-6, pointing to a fundamental difference between human and murine IL-6. So far, it is unclear whether this difference explains the species specificity of human and murine IL-6; whereas human IL-6 binds to both, human and murine IL-6R, murine IL-6 exclusively binds to the murine IL-6R.

Gp130 is a glycosylated type I membrane protein of 130–150 kDa with 6 extracellular domains, a single transmembrane domain, and a
cytoplasmic domain. Gp130 has an N-terminal Ig-like-domain (D1), followed by two cytokine binding domains (CBD; domain 2 and domain 3) and three fibronectin-like (FN III)-domains (domains 4–6). In addition to the physical interaction of gp130 and IL-6R, the Iglike domain of gp130 binds to site 3 of IL-6 and the CBM-domains of gp130 interacting with site 2 of IL-6. The N-terminally located CBM-domain (domain 2) contains two pairs of conserved cysteines that form interstrand disulfide bonds. The C-terminally located domain 3 contains a conserved Trp-Ser-X-Trp-Ser (WSXWS) motif.

After ligand binding, the signaling complex is rapidly internalized, mediated by dileucine-like-motifs in the cytoplasmic domain of gp130. No internalization motifs have been identified within the cytoplasmic portion of the IL-6R. Interestingly, caspase activation by CD95L leads to degradation of the gp130 receptor chain and thereby to blunting of IL-6 signaling.

Other IL-6 Family Receptors

Functional receptor complexes for other IL-6 family of cytokines share the same subunit, known as gp130. The other subunit includes IL-11 receptor alpha (IL11RA), ciliary neurotrophic factor receptor (CNTFR) and leukemia inhibitory factor receptor (LIFR). Unlike other IL-6 family members, IL-31 and leptin do not engage gp130.
IL-31, its receptor heterodimer consists of a unique gp130-like receptor chain IL-31RA, and the receptor subunit OSMRβ that is shared with another family member oncostatin M (OSM).
leptin, its receptor (Leptin Receptor) is homologous to gp130. Both Janus kinases and signal transducers and activators of transcription are involved as downstream components of leptin and IL-6 signaling, which demonstrates several similarities between leptin and the IL-6 family.
These IL-6 family receptors and gp130 are essential for development, hematopoiesis, cell survival and growth.

4. IL-36 receptor complex: IL-1R6

IL-1R6 was identified in 1996 as an interleukin-1 receptor related protein of 561 amino acids, and called IL 1Rrp2. IL-1 R6 binds IL-1F9 and activates NF-kappa B, and that such activation was inhibited by IL-36Ra (IL-1F5). Cell activation by IL-36 through IL-1R6 requires, as for other IL- 1R complexes, the recruitment of a signalling accessory chain, the promiscuous IL-1R3, leading to activation of both NFB and MAP kinases.

References

1. Hunter, C. A., & Jones, S. A. (2015). IL-6 as a keystone cytokine in health and disease. Nature immunology, 16(5), 448-457.
2. Taga, T., & Kishimoto, T. (1997). Gp130 and the interleukin-6 family of cytokines. Annual review of immunology, 15(1), 797-819.
3. Heinrich, P. C., Behrmann, I., Müller-Newen, G., Schaper, F., & Graeve, L. (1998). Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochemical journal, 334(2), 297-314.