Recombinant Human ISG15 Protein

Beta LifeScience SKU/CAT #: BLPSN-3019

Recombinant Human ISG15 Protein

Beta LifeScience SKU/CAT #: BLPSN-3019
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Product Overview

Tag N/A
Host Species Human
Accession AAH09507.1
Synonym G1P2, hUCRP, IFI15, IMD38, IP17, UCRP
Background Interferon-induced 17 kDa protein (ISG15), a 15-kDa protein of unique primary amino acid sequence, functions intracellularly as an ubiquitin homologue and a cytokine that induces production of IFN-gamma and augments NK / lymphokine-activated killer cell proliferation and function. ISG15 is secreted from monocytes and lymphocytes. ISG15 is an ubiquitin-like molecule that is strongly upregulated by type I interferons as a primary response to diverse microbial and cellular stress stimuli. Alterations in the ISG15 signalling pathway have also been found in several human tumour entities. In addition to being stimulated by type I interferon, expression of ISG15 is greatly induced by viral or bacterial infection through the Janus kinase / signal transducer and activator of transcription (Jak / STAT) signalling pathway. After induction, ISG15 is secreted by monocytes, B- and T-lymphocytes and fibroblasts. We demonstrate the novel way in which the function of the ISG15 protein is inhibited by influenza B virus, which strongly induces the ISG15 protein: a specific region of the influenza B virus NS1 protein, which includes part of its effector domain, blocks the covalent linkage of ISG15 to its target proteins both in vitro and in infected cells.
Description A DNA sequence encoding the Pro form of human ISG15 (AAH09507.1) (Met 1-Ser 165) was expressed and purified
Source E.coli
Predicted N Terminal Met 1
AA Sequence Met 1-Ser 165
Molecular Weight The recombinant human ISG15 consisting of 165 a.a. and has a calculated molecular mass of 17.9 kDa. It migrates as an approximately 16 kDa band in SDS-PAGE under reducing conditions.
Purity >97% as determined by SDS-PAGE
Endotoxin Please contact us for more information.
Bioactivity Please contact us for detailed information
Formulation Lyophilized from sterile 50mM Tris, pH 8.0.
Stability The recombinant proteins are stable for up to 1 year from date of receipt at -70°C.
Usage For Research Use Only
Storage Store the protein under sterile conditions at -20°C to -80°C. It is recommended that the protein be aliquoted for optimal storage. Avoid repeated freeze-thaw cycles.

Target Details

Target Function Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Isgylation of the viral sensor IFIH1/MDA5 promotes IFIH1/MDA5 oligomerization and triggers activation of innate immunity against a range of viruses, including coronaviruses, flaviviruses and picornaviruses. Can also isgylate: EIF2AK2/PKR which results in its activation, DDX58/RIG-I which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL.
Subcellular Location Cytoplasm. Secreted. Note=Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins.
Database References
Associated Diseases Immunodeficiency 38, with basal ganglia calcification (IMD38)
Tissue Specificity Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons. Expressed in neutrophils, monocytes and lymphocytes. Enhanced expression seen in pancreatic adenocarcinoma, endometrial cancer, and bladder cancer, as compared to non-c

Gene Functions References

  1. These results demonstrate that virus-induced IFN-lambda4 potently blocks IFN-alpha signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-alpha responsiveness in HCV-infected cells. PMID: 28630501
  2. IFN-gamma increases free ISG15 levels in the cytoplasm and ISGylation in the nucleus and cytoplasm, but in a manner distinct between MCF-7 and MDA-MB-231cells. PMID: 29626479
  3. Hepatitis E virus may promote production of IFN-alpha/beta and expression of ISG15 via ORF3 in the early stages, and increased ISG15 subsequently inhibited the production of IFN-alpha/beta. PMID: 29853735
  4. ISGylation is a ubiquitin-like modification that controls exosome release. ISGylation induction decreases microvesicular body numbers and impairs exosome secretion. Specifically, ISGylation of the MVB protein TSG101 induces its aggregation and degradation, being sufficient to impair exosome secretion. PMID: 27882925
  5. The species-specific gain-of-function in antiviral immunity observed in ISG15 deficiency is explained by the requirement of ISG15 to sustain USP18 levels in humans. PMID: 27193971
  6. HIV-1 IIIB infection of myeloid ThP-1 cells also reduced the IFN-alpha-mediated induction of the anti-viral gene, ISG15, but not MxA, revealing a functional consequence of this HIV-1-mediated immune evasion strategy. PMID: 29580840
  7. DNA damage induces ISG15 conjugation to p53 and this modification markedly enhances the binding of p53 to the promoters of its target genes as well as of its own gene by promoting phosphorylation and acetylation. PMID: 27545325
  8. Studied foot-and-mouth disease virus (FMDV) Lbpro targeting of ISG15. Show a previously undescribed mechanism by which viruses interfere with the ubiquitin and ubiquitin-like systems. PMID: 29463763
  9. ISG15 is able to trigger IFN-gamma production and other signaling pathways suggesting it is a potential cytokine that could interact with still unknown receptors. (Review) PMID: 28467275
  10. ISG15 induces cancer cell apoptosis by disrupting the NF-kappaB signaling pathway. This study highlighted a novel role of ISG15 in tumor suppression. PMID: 27659523
  11. The Interferon-stimulated 15-KDa protein (ISG15) rs1921 variant and ISG15 expression are associated with HBV-related liver diseases. PMID: 27626177
  12. findings revealed that MERS-CoV PLpro chiefly engages human ISG15 through its C-terminal domain; structure of MERS-CoV PLpro was solved to 2.4 A in complex with the C-terminal domain of hISG15; structure of MERS-CoV PLpro in complex with this domain exposed the interface between these two entities PMID: 28931677
  13. Our study demonstrates a protumor role of ISG15, and suggests that ISG15 is a prognostic predictor and a potential therapeutic target for nasopharyngeal carcinoma PMID: 26919245
  14. Results show that HERC5 mediates covalent ISG15 conjugation to parkin in mammalian cells and that ISG15 is conjugated to the Lys349 and Lys369 residues of parkin which increases its ubiquitin E3 ligase activity. PMID: 27534820
  15. Extracellular ISG15 signals cytokine secretion through the LFA-1 integrin receptor (CD11a/CD18) in natural killer cells. PMID: 29100055
  16. Results suggest that unconjugated ISG15 affects the functions of HCV NS5A through protein-protein interaction. PMID: 28543875
  17. This report demonstrates that ISG15 induced by Hepatitis E virus replication in Huh7-S10-3 human liver cells plays an immunomodulatory role by negatively regulating type I Interferon signaling and, thus, Hepatitis E virus sensitivity to type I Interferon. PMID: 28724761
  18. epletion of either ISG15 or UBE2L6/UBCH8 resulted in enhanced endogenous autophagic flux. PMID: 28186990
  19. unlike ISG15, ubiquitin and FAT10 are conjugated to a similar degree to newly translated and pre-existing proteins. PMID: 27926780
  20. This paper shows that ISG15 directly regulates Human Cytomegalovirus replication and that its accumulation restricts productive virus growth. PMID: 28202760
  21. The results suggest that integrin-adhesion-induced MRTF-A-SRF activation and ISG15 expression constitute a newly discovered signaling circuit that promotes cell migration and invasion. PMID: 26872785
  22. These data indicate that hepatic expression of PSMA6, which is upregulated during viral hepatitis, likely depends on TLR3 activation and, that PSMA6 affects the expression of immunoregulatory ISG15, a proviral factor in the pathogenesis of hepatitis C virus infection. PMID: 26833585
  23. ISG15 dysregulation may be involved in the pathogenesis of glomerular inflammation PMID: 26844778
  24. This study shows that interferon-stimulated gene 15 (ISG15) lowers Human respiratory syncytial virus growth through protein ISGylation. PMID: 26763998
  25. Data show the induction of signal transducer and activator of transcription (STAT)1 and IFN-stimulated gene 15 protein (ISG15) in Rickettsia conorii-infected human umbilical vein endothelial cells (HUVECs). PMID: 26560068
  26. ISG15 might serve as a novel prognostic biomarker in drinkers with esophageal squamous cell cancer PMID: 26617815
  27. Cellular ubiquitin is a substrate of ISG15 and Lys 29 on ubiquitin is the major ISG15 acceptor site. PMID: 26226047
  28. Microparticles released from Mycobacterium tuberculosis-infected human macrophages contain increased levels of the type I interferon inducible protein ISG15. PMID: 26036210
  29. The inhibitory effect of ISG15 on HCV RNA replication does not require its conjugation to substrates by HERC5. PMID: 26361997
  30. These data reveal a previously uncharacterized ISG15-dependent restriction of Listeria infection, reinforcing the view that ISG15 is a key component of the innate immune response. PMID: 26259872
  31. free ISG15 may have antitumor and immunoregulatory function in vivo in breast cancer PMID: 25749047
  32. Propose that Isg15-dependent degradation of p53 represents an alternative mechanism of controlling p53 protein levels, and, thus, it is an attractive pathway for drug discovery. PMID: 24844324
  33. Reovirus T3D infection induced STAT-1, ISG-15, IFIT-1, Mx1, and IFIT-3 expression. PMID: 25905045
  34. Results suggest that high ISG15 expression is an intrinsic feature of hepatocellular carcinoma and a trigger for tumorigenesis and metastasis. PMID: 25238261
  35. our work demonstrates that ISG15 is a previously unrecognized support factor for CSC in the PDAC microenvironment with a key role in pathogenesis and progression. PMID: 25368022
  36. intracellular ISG15 is IFN-alpha/beta-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-alpha/beta and prevention of IFN-alpha/beta-dependent autoinflammation PMID: 25307056
  37. The ISG15 conjugation system represents a critical innate response mechanism in cardiomyocytes to fight the battle against invading pathogens, limiting inflammatory cardiomyopathy, heart failure, and death. PMID: 25165091
  38. suppression of ISG15 by siRNA sensitized A549-CUG2 cells to vesicular stomatitis virus infection. PMID: 24452380
  39. ISG15 does not appear to play a key role in IFN-beta-mediated C2C12 myoblast cell fusion PMID: 23750257
  40. ISG15 is a potential prognostic marker in high-grade serous carcinoma of the ovary PMID: 24300530
  41. Results showed that ISG15 modification (ISGylation) of PCNA plays a key role in translesion DNA synthesis termination. PMID: 24768535
  42. These data support the interferon-induced generation of a Tsg101- and ISG15-dependent checkpoint in the secretory pathway that compromises influenza virus release. PMID: 24237697
  43. Findings support the development of ISG15 conjugation inhibitors for treating breast and also other cancers expressing oncogenic Ki-Ras. PMID: 23318454
  44. expression of the ISG15 and/or ISGylation system attenuates HIF-1alpha-mediated gene expression and tumorigenic growth. PMID: 24056783
  45. ISG15 is counteracted by vaccinia virus E3 protein and controls the proinflammatory response against viral infection. PMID: 24257616
  46. Our results suggest that ISG15 overexpression could be developed into a powerful gene-therapeutic tool for treating IFN-alpha-resistant HCC. PMID: 24024201
  47. HIV-1 infection up-regulating expression of ISG15 in cell lines. PMID: 24386835
  48. High interferon-stimulated gene ISG-15 expression affects HCV treatment outcome in patients co-infected with HIV and HCV. PMID: 23588721
  49. Activation of double-stranded RNA-activated protein kinase (PKR) by interferon-stimulated gene 15 (ISG15) modification down-regulates protein translation PMID: 23229543
  50. ISG15 deregulates autophagy in genotoxin-treated ataxia telangiectasia cells PMID: 23212917


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Proteins are sensitive to heat, and freeze-drying can preserve the activity of the majority of proteins. It improves protein stability, extends storage time, and reduces shipping costs. However, freeze-drying can also lead to the loss of the active portion of the protein and cause aggregation and denaturation issues. Nonetheless, these adverse effects can be minimized by incorporating protective agents such as stabilizers, additives, and excipients, and by carefully controlling various lyophilization conditions.

Commonly used protectant include saccharides, polyols, polymers, surfactants, some proteins and amino acids etc. We usually add 8% (mass ratio by volume) of trehalose and mannitol as lyoprotectant. Trehalose can significantly prevent the alter of the protein secondary structure, the extension and aggregation of proteins during freeze-drying process; mannitol is also a universal applied protectant and fillers, which can reduce the aggregation of certain proteins after lyophilization.

Our protein products do not contain carrier protein or other additives (such as bovine serum albumin (BSA), human serum albumin (HSA) and sucrose, etc., and when lyophilized with the solution with the lowest salt content, they often cannot form A white grid structure, but a small amount of protein is deposited in the tube during the freeze-drying process, forming a thin or invisible transparent protein layer.

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