UniProt functional annotation for P01584



	UniProt functional annotation for P01584

UniProt code: P01584.

Organism: Homo sapiens (Human).

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

Function: Potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B- cell activation and antibody production, and fibroblast proliferation and collagen production. Promotes Th17 differentiation of T-cells. Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T- helper 1 (Th1) cells (PubMed:10653850). Plays a role in angiogenesis by inducing VEGF production synergistically with TNF and IL6 (PubMed:12794819). {ECO:0000269|PubMed:10653850, ECO:0000269|PubMed:12794819, ECO:0000269|PubMed:3920526}.

Subunit: Monomer. In its precursor form, weakly interacts with full- length MEFV; the mature cytokine does not interact at all (PubMed:17431422). Interacts with integrins ITGAV:ITGBV and ITGA5:ITGB1; integrin-binding is required for IL1B signaling (PubMed:29030430). Interacts with cargo receptor TMED10; the interaction is direct and is required for the secretion of IL1B mature form (PubMed:32272059). Interacts with HSP90AB1; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059). Interacts with HSP90B1; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059). {ECO:0000269|PubMed:17431422, ECO:0000269|PubMed:20802483, ECO:0000269|PubMed:29030430, ECO:0000269|PubMed:32272059}.

Subcellular location: Cytoplasm, cytosol {ECO:0000269|PubMed:15192144}. Lysosome {ECO:0000269|PubMed:15192144}. Secreted, extracellular exosome {ECO:0000250|UniProtKB:P10749}. Secreted {ECO:0000269|PubMed:11728343, ECO:0000269|PubMed:15192144}. Note=The precursor is cytosolic. In response to inflammasome-activating signals, such as ATP for NLRP3 inflammasome or bacterial flagellin for NLRC4 inflammasome, cleaved and secreted. IL1B lacks any known signal sequence and the pathway(s) of its secretion is(are) not yet fully understood (PubMed:24201029). On the basis of experimental results, several unconventional secretion mechanisms have been proposed. 1. Secretion via secretory lysosomes: a fraction of CASP1 and IL1B precursor may be incorporated, by a yet undefined mechanism, into secretory lysosomes that undergo Ca(2+)- dependent exocytosis with release of mature IL1B (PubMed:15192144). 2. Secretory autophagy: IL1B-containing autophagosomes may fuse with endosomes or multivesicular bodies (MVBs) and then merge with the plasma membrane releasing soluble IL1B or IL1B-containing exosomes (PubMed:24201029). However, autophagy impacts IL1B production at several levels and its role in secretion is still controversial. 3. Secretion via exosomes: ATP-activation of P2RX7 leads to the formation of MVBs containing exosomes with entrapped IL1B, CASP1 and other inflammasome components. These MVBs undergo exocytosis with the release of exosomes. The release of soluble IL1B occurs after the lysis of exosome membranes (By similarity). 4. Secretion by microvesicle shedding: activation of the ATP receptor P2RX7 may induce an immediate shedding of membrane-derived microvesicles containing IL1B and possibly inflammasome components. The cytokine is then released in the extracellular compartment after microvesicle lysis (PubMed:11728343). 5. Release by translocation through permeabilized plasma membrane. This may occur in cells undergoing pyroptosis due to sustained activation of the inflammasome (By similarity). 6. The secretion is dependent on protein unfolding and facilitated by the cargo receptor TMED10; it results in the protein translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) followed by vesicle entry and secretion, and enhanced by chaperones HSP90AB1 and HSP90B1/GRP9 (PubMed:32272059). These mechanisms may not be mutually exclusive. {ECO:0000250|UniProtKB:P10749, ECO:0000269|PubMed:11728343, ECO:0000269|PubMed:15192144, ECO:0000269|PubMed:32272059, ECO:0000305|PubMed:24201029}.

Tissue specificity: Expressed in activated monocytes/macrophages (at protein level). {ECO:0000269|PubMed:15192144}.

Induction: By LPS (PubMed:15192144). Transcription and translation induced by M.tuberculosis and a number of different M.tuberculosis components in macrophages; EsxA is the most potent activator tested (at protein level) (PubMed:20148899). In pancreatic islets, release is increased by high glucose treatment. In pancreatic islets and macrophages, release is also increased by endocannabinoid anandamide/AEA (PubMed:23955712). {ECO:0000269|PubMed:15192144, ECO:0000269|PubMed:20148899, ECO:0000269|PubMed:23955712}.

Ptm: Activation of the IL1B precursor involves a CASP1-catalyzed proteolytic cleavage. Processing and secretion are temporarily associated. {ECO:0000269|PubMed:15192144}.

Miscellaneous: The IL1B production occurs in 2 steps, each being controlled by different stimuli. First, inflammatory signals, such as LPS, stimulate the synthesis and promote the accumulation of cytosolic stores of pro-IL1B (priming). Then additional signals are required for inflammasome assembly, leading to CASP1 activation, pro-IL1B processing and eventually secretion of the active cytokine. IL1B processing and secretion are temporarily associated. {ECO:0000269|PubMed:15192144}.

Similarity: Belongs to the IL-1 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:		Potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B- cell activation and antibody production, and fibroblast proliferation and collagen production. Promotes Th17 differentiation of T-cells. Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T- helper 1 (Th1) cells (PubMed:10653850). Plays a role in angiogenesis by inducing VEGF production synergistically with TNF and IL6 (PubMed:12794819). {ECO:0000269\|PubMed:10653850, ECO:0000269\|PubMed:12794819, ECO:0000269\|PubMed:3920526}.


Subunit:		Monomer. In its precursor form, weakly interacts with full- length MEFV; the mature cytokine does not interact at all (PubMed:17431422). Interacts with integrins ITGAV:ITGBV and ITGA5:ITGB1; integrin-binding is required for IL1B signaling (PubMed:29030430). Interacts with cargo receptor TMED10; the interaction is direct and is required for the secretion of IL1B mature form (PubMed:32272059). Interacts with HSP90AB1; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059). Interacts with HSP90B1; the interaction facilitates cargo translocation into the ERGIC (PubMed:32272059). {ECO:0000269\|PubMed:17431422, ECO:0000269\|PubMed:20802483, ECO:0000269\|PubMed:29030430, ECO:0000269\|PubMed:32272059}.
Subcellular location:		Cytoplasm, cytosol {ECO:0000269\|PubMed:15192144}. Lysosome {ECO:0000269\|PubMed:15192144}. Secreted, extracellular exosome {ECO:0000250\|UniProtKB:P10749}. Secreted {ECO:0000269\|PubMed:11728343, ECO:0000269\|PubMed:15192144}. Note=The precursor is cytosolic. In response to inflammasome-activating signals, such as ATP for NLRP3 inflammasome or bacterial flagellin for NLRC4 inflammasome, cleaved and secreted. IL1B lacks any known signal sequence and the pathway(s) of its secretion is(are) not yet fully understood (PubMed:24201029). On the basis of experimental results, several unconventional secretion mechanisms have been proposed. 1. Secretion via secretory lysosomes: a fraction of CASP1 and IL1B precursor may be incorporated, by a yet undefined mechanism, into secretory lysosomes that undergo Ca(2+)- dependent exocytosis with release of mature IL1B (PubMed:15192144). 2. Secretory autophagy: IL1B-containing autophagosomes may fuse with endosomes or multivesicular bodies (MVBs) and then merge with the plasma membrane releasing soluble IL1B or IL1B-containing exosomes (PubMed:24201029). However, autophagy impacts IL1B production at several levels and its role in secretion is still controversial. 3. Secretion via exosomes: ATP-activation of P2RX7 leads to the formation of MVBs containing exosomes with entrapped IL1B, CASP1 and other inflammasome components. These MVBs undergo exocytosis with the release of exosomes. The release of soluble IL1B occurs after the lysis of exosome membranes (By similarity). 4. Secretion by microvesicle shedding: activation of the ATP receptor P2RX7 may induce an immediate shedding of membrane-derived microvesicles containing IL1B and possibly inflammasome components. The cytokine is then released in the extracellular compartment after microvesicle lysis (PubMed:11728343). 5. Release by translocation through permeabilized plasma membrane. This may occur in cells undergoing pyroptosis due to sustained activation of the inflammasome (By similarity). 6. The secretion is dependent on protein unfolding and facilitated by the cargo receptor TMED10; it results in the protein translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) followed by vesicle entry and secretion, and enhanced by chaperones HSP90AB1 and HSP90B1/GRP9 (PubMed:32272059). These mechanisms may not be mutually exclusive. {ECO:0000250\|UniProtKB:P10749, ECO:0000269\|PubMed:11728343, ECO:0000269\|PubMed:15192144, ECO:0000269\|PubMed:32272059, ECO:0000305\|PubMed:24201029}.
Tissue specificity:		Expressed in activated monocytes/macrophages (at protein level). {ECO:0000269\|PubMed:15192144}.
Induction:		By LPS (PubMed:15192144). Transcription and translation induced by M.tuberculosis and a number of different M.tuberculosis components in macrophages; EsxA is the most potent activator tested (at protein level) (PubMed:20148899). In pancreatic islets, release is increased by high glucose treatment. In pancreatic islets and macrophages, release is also increased by endocannabinoid anandamide/AEA (PubMed:23955712). {ECO:0000269\|PubMed:15192144, ECO:0000269\|PubMed:20148899, ECO:0000269\|PubMed:23955712}.
Ptm:		Activation of the IL1B precursor involves a CASP1-catalyzed proteolytic cleavage. Processing and secretion are temporarily associated. {ECO:0000269\|PubMed:15192144}.
Miscellaneous:		The IL1B production occurs in 2 steps, each being controlled by different stimuli. First, inflammatory signals, such as LPS, stimulate the synthesis and promote the accumulation of cytosolic stores of pro-IL1B (priming). Then additional signals are required for inflammasome assembly, leading to CASP1 activation, pro-IL1B processing and eventually secretion of the active cytokine. IL1B processing and secretion are temporarily associated. {ECO:0000269\|PubMed:15192144}.
Similarity:		Belongs to the IL-1 family. {ECO:0000305}.