IL6ST
Domain
The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.
The box 1 motif is required for JAK interaction and/or activation.
Function
Signal-transducing molecule (PubMed:2261637). The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize IL6ST for initiating signal transmission. Binding of IL6 to IL6R induces IL6ST homodimerization and formation of a high-affinity receptor complex, which activates the intracellular JAK-MAPK and JAK-STAT3 signaling pathways (PubMed:19915009, PubMed:2261637, PubMed:23294003). That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3 (PubMed:19915009, PubMed:23294003, PubMed:25731159). In parallel, the IL6 signaling pathway induces the expression of two cytokine receptor signaling inhibitors, SOCS1 and SOCS3, which inhibit JAK and terminate the activity of the IL6 signaling pathway as a negative feedback loop (By similarity). Also activates the yes-associated protein 1 (YAP) and NOTCH pathways to control inflammation-induced epithelial regeneration, independently of STAT3 (By similarity). Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL27RA/WSX1 and CNTFR (PubMed:19386761). Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism (By similarity). Has a role in embryonic development (By similarity). Essential for survival of motor and sensory neurons and for differentiation of astrocytes (By similarity). Required for expression of TRPA1 in nociceptive neurons (By similarity). Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation (By similarity). Required for normal trabecular bone mass and cortical bone composition (By similarity).
Isoform 2
Binds to the soluble IL6:sIL6R complex (hyper-IL6), thereby blocking IL6 trans-signaling. Inhibits sIL6R-dependent acute phase response (PubMed:11121117, PubMed:21990364, PubMed:30279168). Also blocks IL11 cluster signaling through IL11R (PubMed:30279168).
Involvement in disease
Hyper-IgE syndrome 4A, autosomal dominant, with recurrent infections
HIES4A
An immunologic disorder characterized by recurrent mainly sino-pulmonary infections associated with increased serum IgE. Some patients have onset of symptoms in early childhood and develop complications, including bronchiectasis or hemoptysis, whereas others have later onset of less severe infections. Immunologic workup usually shows normal leukocyte levels, although some patients may demonstrate alterations in lymphocyte subsets, including T cells. Affected individuals also have variable skeletal abnormalities, including high-arched palate, hyperextensible joints, scoliosis, and bone fractures.
None
The disease is caused by variants affecting the gene represented in this entry.
Hyper-IgE syndrome 4B, autosomal recessive, with recurrent infections
HIES4B
An immunologic disorder characterized by recurrent infections, mainly affecting the respiratory tract, skin and eye, and skeletal abnormalities including craniosynostosis and scoliosis. Immunologic workup shows increased serum IgE, intermittent eosinophilia, impaired development of certain B- and T-cell populations, as well as impaired acute-phase response. Disease onset is in early childhood.
None
The disease is caused by variants affecting the gene represented in this entry.
Stuve-Wiedemann syndrome 2
STWS2
A form of Stuve-Wiedemann syndrome, an autosomal recessive disease characterized by bowing of tubular bones and other skeletal and craniofacial abnormalities, respiratory distress, feeding difficulties, and hyperthermic episodes. Most patients do not survive past infancy. STWS2 patients manifest skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response.
None
The disease is caused by variants affecting the gene represented in this entry.
Immunodeficiency 94 with autoinflammation and dysmorphic facies
IMD94
An autosomal dominant disorder characterized by onset in early infancy, lymphadenopathy, autoinflammation, immunodeficiency with hypogammaglobulinemia, and dysmorphic facial features.
None
The disease may be caused by variants affecting the gene represented in this entry.
Post-translational modifications
Phosphorylation of Ser-782 down-regulates cell surface expression.
Heavily N-glycosylated (PubMed:11098061, PubMed:11251120, PubMed:16335952, PubMed:19139490, PubMed:19159218). Glycosylation is required for protein stability and localization in plasma membrane but not for ligand binding (PubMed:19915009).
Sequence Similarities
Belongs to the type I cytokine receptor family. Type 2 subfamily.
Tissue Specificity
Found in all the tissues and cell lines examined (PubMed:2261637). Expression not restricted to IL6 responsive cells (PubMed:2261637).
Isoform 2
Expressed in blood serum (at protein level) (PubMed:24629561).
Cellular localization
- Isoform 1
- Cell membrane
- Single-pass type I membrane protein
- Isoform 2
- Secreted
Alternative names
CD130, Interleukin-6 receptor subunit beta, IL-6 receptor subunit beta, IL-6R subunit beta, IL-6R-beta, IL-6RB, CDw130, Interleukin-6 signal transducer, Membrane glycoprotein 130, Oncostatin-M receptor subunit alpha, gp130, IL6ST