IL6R

Domain

The two fibronectin type-III-like domains, contained in the N-terminal part, form together a cytokine-binding domain.

The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.

Function

Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal (PubMed:28265003). Signal activation necessitate an association with IL6ST. Activation leads to the regulation of the immune response, acute-phase reactions and hematopoiesis (PubMed:30995492, PubMed:31235509). The interaction with membrane-bound IL6R and IL6ST stimulates 'classic signaling', the restricted expression of the IL6R limits classic IL6 signaling to only a few tissues such as the liver and some cells of the immune system. Whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable).

Isoform 1

Signaling via the membrane-bound IL6R is mostly regenerative and anti-inflammatory (Probable). Drives naive CD4(+) T cells to the Th17 lineage, through 'cluster signaling' by dendritic cells (By similarity).

Isoform 2

Soluble form of IL6 receptor (sIL6R) that acts as an agonist of IL6 activity (PubMed:21990364). The IL6:sIL6R complex (hyper-IL6) binds to IL6ST/gp130 on cell surfaces and induces signaling also on cells that do not express membrane-bound IL6R in a process called IL6 'trans-signaling'. sIL6R is causative for the pro-inflammatory properties of IL6 and an important player in the development of chronic inflammatory diseases (PubMed:21990364). In complex with IL6, is required for induction of VEGF production (PubMed:12794819). Plays a protective role during liver injury, being required for maintenance of tissue regeneration (By similarity). 'Trans-signaling' in central nervous system regulates energy and glucose homeostasis (By similarity).

Soluble interleukin-6 receptor subunit alpha

Involvement in disease

Hyper-IgE syndrome 5, autosomal recessive, with recurrent infections

HIES5

An immunologic disorder characterized by recurrent sinopulmonary and deep skin infections, mostly caused by bacteria, including H. influenza and Staphylococcus aureus. Additional features include asthma, atopic dermatitis, and impaired inflammatory responses during infection. Disease onset is in early infancy.

None

The disease is caused by variants affecting the gene represented in this entry.

Post-translational modifications

A short soluble form is released from the membrane by proteolysis (PubMed:26876177). The sIL6R is formed mostly by limited proteolysis of membrane-bound receptors, a process referred to as ectodomain shedding, but is also directly secreted from the cells after alternative mRNA splicing (PubMed:26876177, PubMed:28060820). mIL6R is cleaved by the proteases ADAM10 and ADAM17 (PubMed:26876177, PubMed:28060820).

Glycosylated. Glycosylation is dispensable for transport, signaling, and cell-surface turnover. Glycosylation at Asn-55 is a protease-regulatory exosite. Glycosylation is required for ADAM17-mediated proteolysis.

Sequence Similarities

Belongs to the type I cytokine receptor family. Type 3 subfamily.

Tissue Specificity

Isoform 2

Expressed in peripheral blood mononuclear cells and weakly found in urine and serum. 1%-20% of the total sIL6R in plasma is generated by alternative splicing (PubMed:28060820).

Cellular localization

Isoform 1
Cell membrane
Single-pass type I membrane protein
Isoform 2
Secreted
Soluble interleukin-6 receptor subunit alpha
Secreted

Alternative names

CD126, Interleukin-6 receptor subunit alpha, IL-6 receptor subunit alpha, IL-6R subunit alpha, IL-6R-alpha, IL-6RA, IL-6R 1, Membrane glycoprotein 80, gp80, IL6R

Database links

swissprot:P08887 omim:147880 entrezGene:3570

Other research areas

Immuno-oncology