5CHT , 5CHV
41-466: 11274 24110 ENSG00000184979 ENSMUSG00000030107 Q9UMW8 Q9WTV6 NM_017414 NM_011909 NP_059110 NP_036039 Ubiquitin specific peptidase 18 ( USP18 ), also known as UBP43 , is a type I interferon receptor repressor and an isopeptidase . In humans, it is encoded by the USP18 gene. USP18 is induced by the immune response to type I and III interferons, and serves as
82-440: A negative regulator of type I interferon, but not type III interferon. Loss of USP18 results in increased responsiveness to type I interferons and life-threatening autoinflammatory disease in humans due to the negative regulatory function of USP18 in interferon signal transduction . Independent of this activity, USP18 is also a member of the deubiquitinating protease family of enzymes. It is known to remove ISG15 conjugates from
123-885: A PCNA dependent manner over S-phase, necessary to prevent p21 dependent re-replication, as well as in response to UV irradiation. Recent work has now found that in human cell lines SCF degrades p21 towards the end of G1 phase, allowing cells to exit a quiescent state, whilst CRL4 acts to degrade p21 at a much higher rate than SCF over the G1/S transition and subsequently maintain low levels of p21 throughout S-phase. Cytoplasmic p21 expression can be significantly correlated with lymph node metastasis, distant metastases, advanced TNM stage (a classification of cancer staging that stands for: tumor size, describing nearby lymph nodes, and distant metastasis), depth of invasion and OS ( overall survival rate ). A study on immunohistochemical markers in malignant thymic epithelial tumors shows that p21 expression has
164-463: A block to HIV-1 replication. USP18-deficiency is a very rare primary immunodeficiency caused by mutations of the USP18 gene. The inheritance is autosomal recessive . The clinical disease presents in the perinatal period with life-threatening autoinflammation that mimics TORCH infections, but in the absence of infection. The severe inflammation results from a failure to regulate type I IFN activity, and
205-423: A broad range of protein substrates, a process known as deISGylation. The USP18 gene consists of 11 exons that encode a 43 kDa protein. The USP18 protein adopts the characteristic hand-like structure of ubiquitin-specific-proteases (USPs), which consists of a finger, palm and thumb domain . At the interface of the palm and thumb domain lies the catalytic site composed of the cysteine protease triad (cysteine,
246-528: A cluster on chromosome 9. IFN-α is also made synthetically as medication in hairy cell leukemia. The International Nonproprietary Name (INN) for the product is interferon alfa . The recombinant type is interferon alfacon-1 . The pegylated types are pegylated interferon alfa-2a and pegylated interferon alfa-2b . Recombinant feline interferon omega is a form of cat IFN-α (not ω) for veterinary use. The IFN-β proteins are produced in large quantities by fibroblasts . They have antiviral activity that
287-486: A histidine and an aspartate or asparagine). The C-terminus of USP18 is primarily responsible for negative regulation of interferon-I signaling. Following its induction by type I interferons (IFN-Is), USP18 carries out three functional interactions: USP18 inhibits IFN-I signaling by disrupting the receptor complex and the subsequent JAK-STAT signaling pathway . USP18 binds the IFN-receptor 2 subunit (IFNAR2) , leading to
328-1087: A more extensive characterization of avian genomes. Functional lizard type I IFNs can be found in lizard genome databases. Turtle type I IFNs have been purified (references from 1970s needed). They resemble mammalian homologs. The existence of amphibian type I IFNs have been inferred by the discovery of the genes encoding their receptor chains. They have not yet been purified, or their genes cloned. Piscine (bony fish) type I IFN has been cloned first in zebrafish. and then in many other teleost species including salmon and mandarin fish. With few exceptions, and in stark contrast to avian and especially mammalian IFNs, they are present as single genes (multiple genes are however seen in polyploid fish genomes, possibly arising from whole-genome duplication). Unlike amniote IFN genes, piscine type I IFN genes contain introns, in similar positions as do their orthologs, certain interleukins. Despite this important difference, based on their 3-D structure these piscine IFNs have been assigned as Type I IFNs. While in mammalian species all Type I IFNs bind to
369-590: A negatively influenced survival and significantly correlated with WHO (World Health Organization) type B2/B3. When combined with low p27 and high p53, DFS (Disease-Free Survival) decreases. p21 mediates the resistance of hematopoietic cells to an infection with HIV by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus . HIV infected individuals who naturally suppress viral replication have elevated levels of p21 and its associated mRNA. p21 expression affects at least two stages in
410-447: A region that blocks its ability to complex with cyclins and thus prevent CDK activation. Experiments looking at CDK2 activity within single cells have also shown p21 to be responsible for a bifurcation in CDK2 activity following mitosis, cells with high p21 enter a G 0 /quiescent state, whilst those with low p21 continue to proliferate. Follow up work, found evidence that this bistability
451-865: A single receptor complex, the different groups of piscine type I IFNs bind to different receptor complexes. Until now several type I IFNs (IFNa, b, c, d, e, f and h) has been identified in teleost fish with as low as only one subtype in green pufferfish and as many as six subtypes in salmon with an addition of recently identified novel subtype, IFNh in mandarin fish. P21 1AXC , 2ZVV , 2ZVW , 4RJF , 5E0U 1026 12575 ENSG00000124762 ENSMUSG00000023067 P38936 P39689 NM_078467 NM_000389 NM_001220777 NM_001220778 NM_001291549 NM_001111099 NM_007669 NP_001361438 NP_001361439 NP_001361440 NP_001361441 NP_001361442 NP_001104569 NP_031695 p21 (alternatively p21 ), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 ,
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#1732895447861492-472: A single-cell level have demonstrated that pulsatile p53 activity leads to subsequent pulses of p21, and that the strength of p21 activation is cell cycle phase dependent. Moreover, studies of p21-levels in populations of cycling cells, not exposed to DNA damaging agents, have shown that DNA damage occurring in mother cell S-phase can induce p21 accumulation over both mother G2 and daughter G1 phases which subsequently induces cell cycle arrest; this responsible for
533-716: A specific cell surface receptor complex known as the IFN-α receptor ( IFNAR ) that consists of IFNAR1 and IFNAR2 chains. Type I IFNs are found in all mammals, and homologous (similar) molecules have been found in birds, reptiles, amphibians and fish species. IFN-α and IFN-β are secreted by many cell types including lymphocytes ( NK cells , B-cells and T-cells ), macrophages, fibroblasts, endothelial cells, osteoblasts and others. They stimulate both macrophages and NK cells to elicit an anti-viral response, involving IRF3/IRF7 antiviral pathways, and are also active against tumors . Plasmacytoid dendritic cells have been identified as being
574-540: Is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin / CDK complexes , though is primarily associated with inhibition of CDK2 . p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans. p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits
615-402: Is effectively treated with the selective serotonin reuptake inhibitor class of antidepressants. Interferonopathies are a class of hereditary auto-inflammatory and autoimmune diseases characterised by upregulated type 1 interferon and downstream interferon stimulated genes. The symptoms of these diseases fall in a wide clinical spectrum, and often resemble those of viral infections acquired while
656-847: Is involved mainly in innate immune response. Two types of IFN-β have been described, IFN-β1 ( IFNB1 ) and IFN-β3 ( IFNB3 ) (a gene designated IFN-β2 is actually IL-6 ). IFN-ε, -κ, -τ, and -ζ appear, at this time, to come in a single isoform in humans, IFNK . Only ruminants encode IFN-τ, a variant of IFN-ω. So far, IFN-ζ is only found in mice, while a structural homolog, IFN-δ is found in a diverse array of non-primate and non-rodent placental mammals. Most but not all placental mammals encode functional IFN-ε and IFN-κ genes. . IFN-ω, although having only one functional form described to date ( IFNW1 ), has several pseudogenes : IFNWP2 , IFNWP4 , IFNWP5 , IFNWP9 , IFNWP15 , IFNWP18 , and IFNWP19 in humans. Many non-primate placental mammals express multiple IFN-ω subtypes. This subtype of type I IFN
697-825: Is known to be important. Few endogenous regulators have been found to elicit this important regulatory function, such as SOCS1 and Aryl Hydrocarbon Receptor Interacting Protein (AIP). The mammalian types are designated IFN-α (alpha), IFN-β (beta), IFN-κ (kappa), IFN-δ (delta), IFN-ε (epsilon), IFN-τ (tau), IFN-ω (omega), and IFN-ζ (zeta, also known as limitin). Of these types, IFN-α, IFN -ω, and IFN-τ can work across species. The IFN-α proteins are produced mainly by plasmacytoid dendritic cells (pDCs). They are mainly involved in innate immunity against viral infection. The genes responsible for their synthesis come in 13 subtypes that are called IFNA1 , IFNA2 , IFNA4 , IFNA5 , IFNA6 , IFNA7 , IFNA8 , IFNA10 , IFNA13 , IFNA14 , IFNA16 , IFNA17 , IFNA21 . These genes are found together in
738-646: Is not completely understood, the use of IFN-β1 has been found to reduce brain lesions, increase the expression of anti-inflammatory cytokines and reduce T cell infiltration into the brain. One of the major limiting factors in the efficacy of type I interferon therapy are the high rates of side effects. Between 15% - 40% of people undergoing type 1 IFN treatment develop major depressive disorders. Less commonly, interferon treatment has also been associated with anxiety, lethargy, psychosis and parkinsonism. Mood disorders associated with IFN therapy can be reversed by discontinuation of treatment, and IFN therapy related depression
779-412: Is proposed to block the binding of processivity factors necessary for PCNA dependent S-phase DNA synthesis, but not PCNA dependent nucleotide excision repair (NER). As such, p21 acts as an effective inhibitor of S-phase DNA synthesis though permits NER, leading to the proposal that p21 acts to preferentially select polymerase processivity factors depending on the context of DNA synthesis. This protein
820-403: Is termed deISGylation, as the initial conjugation of ISG15 to newly synthesized proteins is termed ISGylation, a process akin to ubiquitination . However, unlike other de-ubiquitinating enzymes, USP18 is specific to ISG15, and exhibits no cross-reactivity with ubiquitin. The consequences of ISGylation and deISGylation are incompletely understood. USP18 is stabilized by ISG15, but independently of
861-537: Is therefore considered a type I interferonopathy. This syndrome was initially described to result in death within weeks of birth. Fortunately, this previously lethal condition was recently demonstrated to be curable with a Janus kinase inhibitor and intensive supportive care. Interferon type I 1itf :24-186 1au1 B:22-187 2hif :24-182 The type-I interferons (IFN) are cytokines which play essential roles in inflammation , immunoregulation , tumor cells recognition, and T-cell responses. In
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#1732895447861902-472: Is underpinned by double negative feedback between p21 and CDK2, where CDK2 inhibits p21 activity via ubiquitin ligase activity. p21 interacts with proliferating cell nuclear antigen ( PCNA ), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. Specifically, p21 has a high affinity for the PIP-box binding region on PCNA, binding of p21 to this region
943-460: Is used by IFN-α to reduce pain; IFN-α interacts with the μ-opioid receptor to act as an analgesic . In mice, IFN-β inhibits immune cell production of growth factors, thereby slowing tumor growth, and inhibits other cells from producing vessel-producing growth factors, thereby blocking tumor angiogenesis and hindering the tumour from connecting into the blood vessel system. In both mice and human, negative regulation of type I interferon signaling
984-851: The US Food and Drug Administration (FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant and pegylated IFNα for clinical use; e.g., IFNα2a ( Roferon-A , Roche), IFNα2b ( Intron-A , Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment of hairy cell leukemia , melanoma , renal cell carcinoma , Kaposi's sarcoma , multiple myeloma , follicular and non-Hodgkin lymphoma, and chronic myelogenous leukemia . Human IFNβ ( Feron , Toray ltd.) has also been approved in Japan to treat glioblastoma , medulloblastoma , astrocytoma , and melanoma . By combining PD-1/PD-L1 inhibitors with type I interferons, researchers aim to tackle multiple resistance mechanisms and enhance
1025-451: The IFN gene cluster is prevalent among 24 cancer types. Notably deletion of this cluster is significantly associated with increased mortality in many cancer types particularly uterus , kidney , and brain cancers. The Cancer Genome Atlas PanCancer analysis also showed that copy number alteration of the IFN gene cluster is significantly associated with decreased overall survival . For instance,
1066-551: The activity of cyclin - CDK2 , - CDK1 , and - CDK4 /6 complexes, and thus functions as a regulator of cell cycle progression at G 1 and S phase . The binding of p21 to CDK complexes occurs through p21's N-terminal domain, which is homologous to the other CIP/KIP CDK inhibitors p27 and p57 . Specifically it contains a Cy1 motif in the N-terminal half, and weaker Cy2 motif in the C-terminal domain that allow it to bind CDK in
1107-511: The bifurcation in CDK2 activity observed in Spencer et al. . p21 is negatively regulated by ubiquitin ligases both over the course of the cell cycle and in response to DNA damage. Specifically, over the G1/S transition it has been demonstrated that the E3 ubiquitin ligase complex SCF induces degradation of p21. Studies have also demonstrated that the E3 ubiquitin ligase complex CRL4 degrades p21 in
1148-491: The child is in utero, although lacking any infectious origin. The aetiology is largely still unknown, but the most common genetic mutations are associated with nucleic acid regulation, leading most researchers to suggest these arise from the failure of antiviral systems to differentiate between host and viral DNA and RNA. Avian type I IFNs have been characterized and preliminarily assigned to subtypes (IFN I, IFN II, and IFN III), but their classification into subtypes should await
1189-420: The displacement of Janus kinase 1 . and the dissociation of the cytokine-receptor complex. This process requires STAT2 to traffic USP18 to the receptor These events terminate signaling and draw cells into a refractory state with diminished sensitivity to future stimulation. Using the isopeptidase domain, USP18 specifically deconjugates ISG15 (interferon-stimulated gene 15) from tagged proteins. This reaction
1230-419: The human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cytoband over approximately 400 kb including coding genes for IFNα ( IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17 and IFNA21 ), IFNω ( IFNW1 ), IFNɛ ( IFNE ), IFNк ( IFNK ) and IFNβ ( IFNB1 ), plus 11 IFN pseudogenes. Interferons bind to interferon receptors . All type I IFNs bind to
1271-495: The innate immune response and establishes disseminated infection. It was reported that human USP18 is a novel factor potentially contributing to HIV replication by blocking the antiviral function of p21 in differentiated human myeloid cells. USP18 downregulates p21 protein expression, which correlates with upregulated intracellular dNTP levels and the antiviral inactive form of SAMHD1. Depletion of USP18 stabilizes p21 protein expression, which correlates with dephosphorylated SAMHD1 and
USP18 - Misplaced Pages Continue
1312-465: The most potent producers of type I IFNs in response to antigen, and have thus been coined natural IFN producing cells. IFN-ω is released by leukocytes at the site of viral infection or tumors. IFN-α acts as a pyrogenic factor by altering the activity of thermosensitive neurons in the hypothalamus thus causing fever. It does this by binding to opioid receptors and eliciting the release of prostaglandin-E 2 (PGE 2 ). A similar mechanism
1353-455: The overall anti-tumor immune response. The approach is supported by preclinical and clinical studies that show promising synergistic effects, particularly in melanoma and renal carcinoma . These studies reveal increased infiltration and activation of T cells within the tumor microenvironment , the development of memory T cells , and prolonged patient survival. Due to their strong antiviral properties, recombinant type 1 IFNs can be used for
1394-422: The overall survival of patients with brain glioma reduced from 93 months (diploidy) to 24 months. In conclusion, the copy number alteration of the IFN gene cluster is associated with increased mortality and decreased overall survival in cancer. From the 1980s onward, members of type-I IFN family have been the standard care as immunotherapeutic agents in cancer therapy. In particular, IFNα has been approved by
1435-409: The primary mediator of downstream cell cycle arrest. Notably, El-Deiry et al. identified a protein p21 (WAF1) which was present in cells expressing wild type p53 but not those with mutant p53, moreover constitutive expression of p21 led to cell cycle arrest in a number of cell types. Dulcic et al. also found that γ-irradiation of fibroblasts induced a p53 and p21 dependent cell cycle arrest, here p21
1476-410: The treatment for persistent viral infection. Pegylated IFN-α is the current standard of care when it comes to chronic Hepatitis B and C infection. Currently, there are four FDA approved variants of IFN-β1 used as a treatment for relapsing multiple sclerosis . IFN-β1 is not an appropriate treatment for patients with progressive, non-relapsing forms of multiple sclerosis. Whilst the mechanism of action
1517-478: The ubiquitin-like conjugation. Without ISG15-mediated stabilization, USP18 is degraded at the proteasome . This relationship exists in human, canine and porcine USP18/ISG15, but is absent in murine systems. Macrophages and dendritic cells are usually the first point of contact with pathogens, including lentiviruses . Host restriction factors, including SAMHD1 , mediate the innate immune response against these viruses. However, HIV-1 has evolved to circumvent
1558-452: Was found bound to inactive cyclin E / CDK2 complexes. Working in mouse models, it was also shown that whilst mice lacking p21 were healthy, spontaneous tumours developed and G1 checkpoint control was compromised in cells derived from these mice. Taken together, these studies thus defined p21 as the primary mediator of p53-dependent cell cycle arrest in response to DNA damage. Recent work exploring p21 activation in response to DNA damage at
1599-450: Was recently described as a pseudogene in human, but potentially functional in the domestic cat genome. In all other genomes of non-feline placental mammals, IFN-ν is a pseudogene; in some species, the pseudogene is well preserved, while in others, it is badly mutilated or is undetectable. Moreover, in the cat genome, the IFN-ν promoter is deleteriously mutated. It is likely that the IFN-ν gene family
1640-1111: Was rendered useless prior to mammalian diversification. Its presence on the edge of the type I IFN locus in mammals may have shielded it from obliteration, allowing its detection. From the 1980s onward, members of type-I IFN family have been the standard care as immunotherapeutic agents in cancer therapy. In particular, IFNα has been approved by the US Food and Drug Administration (FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant and pegylated IFNα for clinical use; e.g., IFNα2a ( Roferon-A , Roche), IFNα2b ( Intron-A , Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment of hairy cell leukemia , melanoma , renal cell carcinoma , Kaposi's sarcoma , multiple myeloma , follicular and non-Hodgkin lymphoma, and chronic myelogenous leukemia . Human IFNβ ( Feron , Toray ltd.) has also been approved in Japan to treat glioblastoma , medulloblastoma , astrocytoma , and melanoma . [1] A large individual patient data meta-analysis using 9937 patients obtained from cBioportal indicates that copy number alteration of
1681-477: Was reported to be specifically cleaved by CASP3 -like caspases , which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation. However p21 may inhibit apoptosis and does not induce cell death on its own. The ability of p21 to inhibit apoptosis in response to replication fork stress has also been reported. Studies of p53 dependent cell cycle arrest in response to DNA damage identified p21 as