ISG15

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.

ISG15 Related Areas

Neuroscience>>Neurodegenerative Disease>>Ubiquitin-proteasome pathway>> ISG15

Enzyme>>Protein Kinase>>Intracellular Kinase>> Jak (Janus Kinase) >> ISG15

ISG15 Alternative Names

G1P2, IFI15, IP17, UCRP, hUCRP[Homo sapiens]

G1p2, IGI15, IP17, Irfp, UCRP[Mus musculus]

Summaries for ISG15

Entrez Gene summary for ISG15:

ISG15 is a ubiquitin-like protein that becomes conjugated to many cellular proteins upon activation by interferon-alpha (IFNA; MIM 147660) and -beta

OMIM - description for ISG15:

ISG15 is a ubiquitin-like protein that becomes conjugated to many cellular proteins upon activation by interferon-alpha

Wikipedia summary for ISG15:

Interferon-induced 17 kDa protein is a protein that in humans is encoded by the ISG15 gene. ISG15 shares several common properties with other ubiquitin-like molecules (UBLs), but its activity is tightly regulated by specific signaling pathways that have a role in innate immunity. ISG15 was identified as an interferon stimulated gene (ISG) since its expression is induced in response to type I interferons or lipopolysaccharide treatment. Upon interferon treatment, ISG15 can be detected in both free and conjugated forms, and is secreted from monocytes and lymphocytes where it can function as a cytokine. In the cell, ISG15 co-localizes with intermediate filaments and ISGylation may modulate the JAK-STAT pathway or certain aspects of neurological disease. It is also known as UCRP (ubiquitin cross-reactive protein) since it contains 2 tandem ubiquitin homology domains and is cross-reactive with ubiquitin antibodies. In contrast to other UBLs, ISG15 has not been identified in lower eukaryotes (yeast, nematode, insects, plants) indicating its role in specialized functions. The mechanism of ISGylation and deISGylation is similar to that of ubiquitin, although the complete system components have not yet been identified. The activating E1 enzyme (UBE1L) charges ISG15 by forming a high-energy thiolester intermediate and transfers it to the UbcH8 E2 protein. UbcH8 has been identified as the major E2 for ISGlyation, although it also functions in ubiquitination. The E2 protein subsequently transfers the ISG15 to specific E3 ligases (none have been identified to date) and relevant intracellular substrates. Only one deconjugating protease with specificity to ISG15 has been identified to date: UBP43 (a member of the USP family) cleaves ISG15-peptide fusions and also removes ISG15 (deISGylation) from native conjugates

Human ISG15 Protein General Information

 

• Protein names: Recommended name: Ubiquitin-like protein ISG15 Alternative name(s): Interferon-induced 15 kDa protein Interferon-induced 17 kDa protein Short name=IP17
• Sequence length: 165 AA.
• Domain: Repeat
• Sequence similarities: Contains 2 ubiquitin-like domains.
• Tissue specificity: Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons.
• Subunit structure: Interacts with, and is conjugated to its targets by the UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) Probable. Interaction with influenza B NS1 protein inhibits this conjugation.
• Subcellular location: Cytoplasm. Secreted. Note: UCRP conjugates seem to be noncovalently associated with the intermediate filaments and distributed in a punctate pattern. Also secreted.
• Induction: By type I interferons.

General information above from UniProt

Function for ISG15 Protein

UniProtKB:

Ubiquitin-like protein that is conjugated to intracellular target proteins after IFN-alpha or IFN-beta stimulation. Its enzymatic pathway is partially distinct from that of ubiquitin, differing in substrate specificity and interaction with ligating enzymes. ISG15 conjugation pathway uses a dedicated E1 enzyme, but seems to converge with the Ub conjugation pathway at the level of a specific E2 enzyme. Targets include STAT1, SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, EIF2AK2/PKR, MX1/MxA, and RIG-1. Deconjugated by USP18/UBP43. Shows specific chemotactic activity towards neutrophils and activates them to induce release of eosinophil chemotactic factors. May serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments. May also be involved in autocrine, paracrine and endocrine mechanisms, as in cell-to-cell signaling, possibly partly by inducing IFN-gamma secretion by monocytes and macrophages. Seems to display antiviral activity during viral infections.

Genatlas:

• ubiquitin-like protein playing a role in immune response
• ISG15 may be associated with specialized functions in innate immune system
• interferon-induced ubiquitin-like modifier, implicated in a variety of biological activities, which encompass antiviral defense, immune responses, and pregnancy
• ISG15 has not essential role for STAT1 signaling and responses against vesicular stomatitis and lymphocytic choriomeningitis virus
• ISG15 interact with, and conjugated to its targets by UBE1L and UBE2E2
• ISG15 enhance the innate antiviral response by inhibition of IRF3 degradation
• ISG15 is involved in the conjugation of FLNB, leading to the release of RAC1, MEKK1 and MKK4 from the scaffold protein and thus blocking the JNK cascade activation (Jeon, 2009)

Homology for human ISG15

• homolog to rattus G1p2 (64.33 pc)