IL6ST gene

The IL6ST gene (IL6ST stands for "Interleukin 6 Cytokine Family Signal Transducer") is a protein coding gene located at chromosome 5q11.2. Alternatively spliced transcript variants have been described. A related pseudogene has been identified on chromosome 17.

The protein encoded by the IL6ST gene (Gp130) functions as part of the cytokine receptor complex. It is a so-called signal transducer shared by many cytokines:

• Interleukin 6 (IL6)
• the ciliary neurotrophic factor (CNTF)
• leukemia inhibitory factor (LIF)
• Oncostatin M (OSM).

The activation of this protein depends on the binding of the cytokines to their receptors. vIL6, a protein related to IL6 and encoded by the Kaposi's sarcoma-associated herpes virus, can bypass the interleukin-6 receptor (IL6R) and activate this protein directly.

The receptor systems for IL-6, LIF, OSM, CNTF, IL-11, CTF1, and BSF3 can utilize the encoded IL6ST protein (Gp130) to initiate signal transduction. Binding of IL-6 to IL6R induces homodimerization of IL6ST and formation of a high-affinity receptor complex that activates intracellular JAK/MAPK and JAK-STAT3 signaling pathways (see Fig.). This activation causes phosphorylation of IL6ST tyrosine residues, a process that in turn activates STAT3 . In parallel, the IL-6 pathway induces the expression of two cytokine receptor signaling inhibitors, SOCS1 and SOCS3, which inhibit JAK. This terminates the activity of the IL6 signaling pathway in the form of a negative feedback loop.

The encoded protein IL6ST also activates the Yes-associated protein 1 (YAP) andNOTCH signaling pathways. This allows inflammation-induced epithelial regeneration to be controlled independently of STAT3.

Furthermore, it mediates signals regulating immune response, hematopoiesis, pain control and bone metabolism. IL6ST plays a role in embryonic development and is essential for motor and sensory neuron survival and astrocyte differentiation, as well as for TRPA1 expression in nociceptive neurons. The protein is required for normal trabecular bone mass and cortical bone composition.

Isoform 2 of the protein binds to the soluble IL6/sIL6R complex (hyper-IL6), thereby blocking IL6 trans-signaling. Inhibits sIL6R-dependent acute phase response and also blocks IL11 cluster signaling through IL11R.

Diseases associated with IL6ST include:

• Hyper-IgE recurrent infection syndrome 4, autosomal recessive

and

• Stüve-Wiedemann syndrome 2 (rare syndrome characterized by short stature, curvature of the extremities, camptodactyly, respiratory distress/apnea attacks, and hyperthermic episodes often associated with feeding/swallowing disorders. Other clinical findings include mask-like face, pursed mouth, hypoplastic midface, osteopenia, congenital contractures, and muscular hypotonia. The condition is fatal in most cases.)

An important paralog of this gene is IL31RA.