UniProt functional annotation for Q9NPH3



	UniProt functional annotation for Q9NPH3

UniProt code: Q9NPH3.

Organism: Homo sapiens (Human).

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

Function: Coreceptor for IL1RL2 in the IL-36 signaling system (By similarity). Coreceptor with IL1R1 in the IL-1 signaling system. Associates with IL1R1 bound to IL1B to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Recruits TOLLIP to the signaling complex. Does not bind to interleukin-1 alone; binding of IL1RN to IL1R1, prevents its association with IL1R1 to form a signaling complex. The cellular response is modulated through a non-signaling association with the membrane IL1R2 decoy receptor. Coreceptor for IL1RL1 in the IL-33 signaling system. Can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to PTPRD (By similarity). May play a role in IL1B-mediated costimulation of IFNG production from T-helper 1 (Th1) cells (Probable). {ECO:0000250|UniProtKB:Q61730, ECO:0000269|PubMed:10799889, ECO:0000269|PubMed:9371760, ECO:0000305|PubMed:10653850, ECO:0000305|PubMed:19836339}.

Function: [Isoform 2]: Associates with secreted ligand-bound IL1R2 and increases the affinity of secreted IL1R2 for IL1B; this complex formation may be the dominant mechanism for neutralization of IL1B by secreted/soluble receptors (PubMed:12530978). Enhances the ability of secreted IL1R1 to inhibit IL-33 signaling (By similarity). {ECO:0000250|UniProtKB:Q61730, ECO:0000269|PubMed:12530978}.

Function: [Isoform 4]: Unable to mediate canonical IL-1 signaling (PubMed:19481478). Required for Src phosphorylation by IL1B. May be involved in IL1B-potentiated NMDA-induced calcium influx in neurons (By similarity). {ECO:0000250|UniProtKB:Q61730, ECO:0000269|PubMed:19481478}.

Catalytic activity: Reaction=H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide; Xref=Rhea:RHEA:16301, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:57967; EC=3.2.2.6; Evidence={ECO:0000255|PROSITE-ProRule:PRU00204}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302; Evidence={ECO:0000255|PROSITE-ProRule:PRU00204};

Subunit: The interleukin-36 receptor complex is a heterodimer of IL1RL2 and IL1RAP; the association is inhibited by IL36RN (By similarity). The interleukin-1 receptor complex is a heterodimer of IL1R1 and IL1RAP. Associates with IL1R2 to form a non-signaling interleukin-1 receptor complex. Isoform 4 interacts with IL1R1 in an interleukin-1-dependent manner. Interacts with IL-33-bound IL1RL1 to form the minimal interleukin-33 signaling complex with a 1:1:1 stoichiometry. Interacts with KIT (independently of stimulation with KITLG/SCF). A mast cell- specific KITLG/SCF-induced interleukin-33 signaling complex contains IL1RL1, IL1RAP, KIT and MYD88 (By similarity). Interacts (via the first immunoglobilin domain) with PTPRD (via the third immunoglobilin domain); induces pre- and postsynaptic differentiation of neurons (By similarity). {ECO:0000250|UniProtKB:Q61730, ECO:0000269|PubMed:19481478, ECO:0000269|PubMed:20802483, ECO:0000269|PubMed:9371760, ECO:0000269|PubMed:9862719, ECO:0000305|PubMed:19836339}.

Subcellular location: [Isoform 1]: Cell membrane; Single-pass type I membrane protein.

Subcellular location: [Isoform 2]: Secreted.

Subcellular location: [Isoform 3]: Secreted.

Tissue specificity: Detected in liver, skin, placenta, thymus and lung. Isoform 4 is predominantly expressed in brain. Overexpressed on candidate chronic myeloid leukemia (CML) stem cells, hematopoietic stem cells and mononuclear cells of patients with acute myeloid leukemia (AML). Overexpressed in patients with chronic obstructive pulmonary disease (COPD). Expressed in T-helper 1 (Th1) and T-helper 2 (Th2) cell subsets (PubMed:10653850). {ECO:0000269|PubMed:10653850, ECO:0000269|PubMed:12530978, ECO:0000269|PubMed:19481478, ECO:0000269|PubMed:20805474, ECO:0000269|PubMed:22723552, ECO:0000269|PubMed:23479569, ECO:0000269|PubMed:25595648}.

Induction: Isoform 1 is down-regulated by phorbol ester treatment. Isoform 2 is induced by phorbol ester treatment. {ECO:0000269|PubMed:10799889, ECO:0000269|PubMed:12781872}.

Domain: The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity. {ECO:0000255|PROSITE-ProRule:PRU00204}.

Miscellaneous: [Isoform 3]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.

Similarity: Belongs to the interleukin-1 receptor family. {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:		Coreceptor for IL1RL2 in the IL-36 signaling system (By similarity). Coreceptor with IL1R1 in the IL-1 signaling system. Associates with IL1R1 bound to IL1B to form the high affinity interleukin-1 receptor complex which mediates interleukin-1-dependent activation of NF-kappa-B and other pathways. Signaling involves the recruitment of adapter molecules such as TOLLIP, MYD88, and IRAK1 or IRAK2 via the respective TIR domains of the receptor/coreceptor subunits. Recruits TOLLIP to the signaling complex. Does not bind to interleukin-1 alone; binding of IL1RN to IL1R1, prevents its association with IL1R1 to form a signaling complex. The cellular response is modulated through a non-signaling association with the membrane IL1R2 decoy receptor. Coreceptor for IL1RL1 in the IL-33 signaling system. Can bidirectionally induce pre- and postsynaptic differentiation of neurons by trans-synaptically binding to PTPRD (By similarity). May play a role in IL1B-mediated costimulation of IFNG production from T-helper 1 (Th1) cells (Probable). {ECO:0000250\|UniProtKB:Q61730, ECO:0000269\|PubMed:10799889, ECO:0000269\|PubMed:9371760, ECO:0000305\|PubMed:10653850, ECO:0000305\|PubMed:19836339}.



Function:		[Isoform 2]: Associates with secreted ligand-bound IL1R2 and increases the affinity of secreted IL1R2 for IL1B; this complex formation may be the dominant mechanism for neutralization of IL1B by secreted/soluble receptors (PubMed:12530978). Enhances the ability of secreted IL1R1 to inhibit IL-33 signaling (By similarity). {ECO:0000250\|UniProtKB:Q61730, ECO:0000269\|PubMed:12530978}.



Function:		[Isoform 4]: Unable to mediate canonical IL-1 signaling (PubMed:19481478). Required for Src phosphorylation by IL1B. May be involved in IL1B-potentiated NMDA-induced calcium influx in neurons (By similarity). {ECO:0000250\|UniProtKB:Q61730, ECO:0000269\|PubMed:19481478}.


Catalytic activity:		Reaction=H2O + NAD(+) = ADP-D-ribose + H(+) + nicotinamide; Xref=Rhea:RHEA:16301, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17154, ChEBI:CHEBI:57540, ChEBI:CHEBI:57967; EC=3.2.2.6; Evidence={ECO:0000255\|PROSITE-ProRule:PRU00204}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16302; Evidence={ECO:0000255\|PROSITE-ProRule:PRU00204};
Subunit:		The interleukin-36 receptor complex is a heterodimer of IL1RL2 and IL1RAP; the association is inhibited by IL36RN (By similarity). The interleukin-1 receptor complex is a heterodimer of IL1R1 and IL1RAP. Associates with IL1R2 to form a non-signaling interleukin-1 receptor complex. Isoform 4 interacts with IL1R1 in an interleukin-1-dependent manner. Interacts with IL-33-bound IL1RL1 to form the minimal interleukin-33 signaling complex with a 1:1:1 stoichiometry. Interacts with KIT (independently of stimulation with KITLG/SCF). A mast cell- specific KITLG/SCF-induced interleukin-33 signaling complex contains IL1RL1, IL1RAP, KIT and MYD88 (By similarity). Interacts (via the first immunoglobilin domain) with PTPRD (via the third immunoglobilin domain); induces pre- and postsynaptic differentiation of neurons (By similarity). {ECO:0000250\|UniProtKB:Q61730, ECO:0000269\|PubMed:19481478, ECO:0000269\|PubMed:20802483, ECO:0000269\|PubMed:9371760, ECO:0000269\|PubMed:9862719, ECO:0000305\|PubMed:19836339}.
Subcellular location:		[Isoform 1]: Cell membrane; Single-pass type I membrane protein.
Subcellular location:		[Isoform 2]: Secreted.
Subcellular location:		[Isoform 3]: Secreted.
Tissue specificity:		Detected in liver, skin, placenta, thymus and lung. Isoform 4 is predominantly expressed in brain. Overexpressed on candidate chronic myeloid leukemia (CML) stem cells, hematopoietic stem cells and mononuclear cells of patients with acute myeloid leukemia (AML). Overexpressed in patients with chronic obstructive pulmonary disease (COPD). Expressed in T-helper 1 (Th1) and T-helper 2 (Th2) cell subsets (PubMed:10653850). {ECO:0000269\|PubMed:10653850, ECO:0000269\|PubMed:12530978, ECO:0000269\|PubMed:19481478, ECO:0000269\|PubMed:20805474, ECO:0000269\|PubMed:22723552, ECO:0000269\|PubMed:23479569, ECO:0000269\|PubMed:25595648}.
Induction:		Isoform 1 is down-regulated by phorbol ester treatment. Isoform 2 is induced by phorbol ester treatment. {ECO:0000269\|PubMed:10799889, ECO:0000269\|PubMed:12781872}.
Domain:		The TIR domain mediates NAD(+) hydrolase (NADase) activity. Self-association of TIR domains is required for NADase activity. {ECO:0000255\|PROSITE-ProRule:PRU00204}.
Miscellaneous:		[Isoform 3]: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. {ECO:0000305}.
Similarity:		Belongs to the interleukin-1 receptor family. {ECO:0000305}.