UniProt functional annotation for P08887



	UniProt functional annotation for P08887

UniProt code: P08887.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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 (Probable). 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). {ECO:0000269|PubMed:28265003, ECO:0000305|PubMed:30995492}.

Function: [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). {ECO:0000250|UniProtKB:P22272, ECO:0000305|PubMed:30995492}.

Function: [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 proinflammatory 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). {ECO:0000250|UniProtKB:P22272, ECO:0000269|PubMed:12794819, ECO:0000269|PubMed:21990364}.

Function: [Soluble interleukin-6 receptor subunit alpha]: 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 proinflammatory 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). {ECO:0000250|UniProtKB:P22272, ECO:0000269|PubMed:12794819, ECO:0000269|PubMed:21990364}.

Activity regulation: Classic and trans-signaling are both inhibited by tocilizumab, a humanized monoclonal antibody that blocks interleukin IL6R signaling. {ECO:0000269|PubMed:21990364}.

Subunit: Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; first binds to IL6 to associate with the signaling subunit IL6ST (PubMed:12829785, PubMed:28265003). Interacts (via N-terminal ectodomain) with SORL1; this interaction may affect IL6-binding to IL6R, hence decrease IL6 'classic-signaling' (PubMed:28265003). {ECO:0000269|PubMed:12829785, ECO:0000269|PubMed:28265003}.

Subunit: [Isoform 2]: Also interacts with SORL1; this interaction leads to soluble IL6R internalization. May form a trimeric complex with the soluble SORL1 ectodomain and circulating IL6 receptor; this interaction might stabilize circulating IL6, hence promote IL6 'trans-signaling,. {ECO:0000269|PubMed:28265003}.

Subunit: [Soluble interleukin-6 receptor subunit alpha]: Also interacts with SORL1; this interaction leads to soluble IL6R internalization. May form a trimeric complex with the soluble SORL1 ectodomain and circulating IL6 receptor; this interaction might stabilize circulating IL6, hence promote IL6 'trans-signaling,. {ECO:0000269|PubMed:28265003}.

Subcellular location: [Isoform 1]: Cell membrane {ECO:0000250|UniProtKB:P22272}; Single-pass type I membrane protein {ECO:0000255}.

Subcellular location: [Isoform 2]: Secreted {ECO:0000269|PubMed:28060820}.

Subcellular location: [Soluble interleukin-6 receptor subunit alpha]: Secreted {ECO:0000269|PubMed:28060820}.

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). {ECO:0000269|PubMed:28060820}.

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

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

Ptm: 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). {ECO:0000269|PubMed:26876177, ECO:0000269|PubMed:28060820}.

Ptm: 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. {ECO:0000269|PubMed:28060820}.

Polymorphism: Genetic variations in IL6R determine soluble IL6R serum levels [MIM:614689].

Polymorphism: Genetic variations in IL6R define the IL6 serum level quantitative trait locus [MIM:614752].

Similarity: Belongs to the type I cytokine receptor family. Type 3 subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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 (Probable). 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). {ECO:0000269\|PubMed:28265003, ECO:0000305\|PubMed:30995492}.



Function:		[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). {ECO:0000250\|UniProtKB:P22272, ECO:0000305\|PubMed:30995492}.



Function:		[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 proinflammatory 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). {ECO:0000250\|UniProtKB:P22272, ECO:0000269\|PubMed:12794819, ECO:0000269\|PubMed:21990364}.



Function:		[Soluble interleukin-6 receptor subunit alpha]: 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 proinflammatory 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). {ECO:0000250\|UniProtKB:P22272, ECO:0000269\|PubMed:12794819, ECO:0000269\|PubMed:21990364}.


Activity regulation:		Classic and trans-signaling are both inhibited by tocilizumab, a humanized monoclonal antibody that blocks interleukin IL6R signaling. {ECO:0000269\|PubMed:21990364}.
Subunit:		Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; first binds to IL6 to associate with the signaling subunit IL6ST (PubMed:12829785, PubMed:28265003). Interacts (via N-terminal ectodomain) with SORL1; this interaction may affect IL6-binding to IL6R, hence decrease IL6 'classic-signaling' (PubMed:28265003). {ECO:0000269\|PubMed:12829785, ECO:0000269\|PubMed:28265003}.
Subunit:		[Isoform 2]: Also interacts with SORL1; this interaction leads to soluble IL6R internalization. May form a trimeric complex with the soluble SORL1 ectodomain and circulating IL6 receptor; this interaction might stabilize circulating IL6, hence promote IL6 'trans-signaling,. {ECO:0000269\|PubMed:28265003}.
Subunit:		[Soluble interleukin-6 receptor subunit alpha]: Also interacts with SORL1; this interaction leads to soluble IL6R internalization. May form a trimeric complex with the soluble SORL1 ectodomain and circulating IL6 receptor; this interaction might stabilize circulating IL6, hence promote IL6 'trans-signaling,. {ECO:0000269\|PubMed:28265003}.
Subcellular location:		[Isoform 1]: Cell membrane {ECO:0000250\|UniProtKB:P22272}; Single-pass type I membrane protein {ECO:0000255}.
Subcellular location:		[Isoform 2]: Secreted {ECO:0000269\|PubMed:28060820}.
Subcellular location:		[Soluble interleukin-6 receptor subunit alpha]: Secreted {ECO:0000269\|PubMed:28060820}.
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). {ECO:0000269\|PubMed:28060820}.
Domain:		The two fibronectin type-III-like domains, contained in the N- terminal part, form together a cytokine-binding domain.
Domain:		The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.
Ptm:		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). {ECO:0000269\|PubMed:26876177, ECO:0000269\|PubMed:28060820}.
Ptm:		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. {ECO:0000269\|PubMed:28060820}.
Polymorphism:		Genetic variations in IL6R determine soluble IL6R serum levels [MIM:614689].
Polymorphism:		Genetic variations in IL6R define the IL6 serum level quantitative trait locus [MIM:614752].
Similarity:		Belongs to the type I cytokine receptor family. Type 3 subfamily. {ECO:0000305}.