ISG15 Gene

Last updated on: 14.12.2023

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General informationThis section has been translated automatically.

The ISG15 gene (ISG15 stands for "Ubiquitin Like Modifier") is a protein-coding gene localized to chromsome 1p36.33. The protein encoded by the ISG15 gene is a ubiquitin-like protein that is attached to intracellular target proteins upon activation by interferon-alpha and interferon-beta. The protein encoded by this gene has chemotactic activity against neutrophils. Furthermore, it causes the alignment of ligated target proteins to intermediate filaments, cell-to-cell signaling and antiviral activity in viral infections.

The ubiquitin-like protein, which plays a key role in the innate immune response to viral infections, develops its effect either through its conjugation to a target protein (ISGylation - Note: "ISGylation" refers to the binding of a specific protein (e.g. STING) with a second, small protein, ISG15) or through its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2 and E3 enzymes that catalyze the conjugation of ISG15 to a lysine residue in the target protein.

The target proteins of the ubiquitin-like protein 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. The encoded protein exhibits antiviral activity against both DNA and RNA viruses (see viruses, classification below), including influenza A, HIV-1 and Ebola virus. Inhibits HIV-1 and Ebola viruses by interrupting viral budding.

The secreted form of ISG15 can induce the proliferation of natural killer cells, act as a chemotactic factor for neutrophils and, as an IFN-gamma-inducing cytokine, play an essential role in antimycobacterial immunity .

Clinical pictureThis section has been translated automatically.

Diseases associated with ISG15 include Immunodeficiency 38 (IMD38; see also Mendelian susceptibility to mycobacterial diseases; see also under Immunodeficiencies) with Basal Ganglia Calcification (OMIM: 616126). Individuals with IMD38 suffer from selective immunodeficiency leading to severe clinical disease when infected with low virulence mycobacteria, including Mycobacterium bovis Bacille Calmette-Guerin (BCG) vaccines (Bogunovic et al. 2012). In contrast, there isno immunodeficiency to viral infections. Affected individuals exhibit intracranial calcification (Zhang et al. 2015).

LiteratureThis section has been translated automatically.

  1. Bogunovic D et al. (2012) Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science 337: 1684-1688.
  2. Zhang X et all. (2015) Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation. Nature 517: 89-93.

Last updated on: 14.12.2023