ISG15
Description
The ISG15 (ISG15 ubiquitin like modifier) is a protein-coding gene located on chromosome 1.
Interferon-stimulated gene 15 (ISG15) is a 17 kDA secreted protein that in humans is encoded by the ISG15 gene. ISG15 is induced by type I interferon (IFN) and serves many functions, acting both as an extracellular cytokine and an intracellular protein modifier. The precise functions are diverse and vary among species but include potentiation of Interferon gamma (IFN-II) production in lymphocytes, ubiquitin-like conjugation to newly-synthesized proteins and negative regulation of the IFN-I response.
== Structure == The ISG15 gene consists of two exons and encodes for a 17 kDa polypeptide. The immature polypeptide is cleaved at its carboxy terminus, generating a mature 15 kDa product that terminates with a LRLRGG motif, as found in ubiquitin. The tertiary structure of ISG15 also resembles ubiquitin, despite only ~30% sequence identity. Specifically, this structure consists of two ubiquitin-like domains connected by a polypeptide ‘hinge.’ Of note, ISG15 shows substantial sequence variation among species, with homology as low as 30% between orthologs.
== Function == After induction by type I interferon, ISG15 can be found in three forms, each with unique functions:
=== Extracellular cytokine === ISG15 is secreted from the cell and can be detected in supernatant or blood plasma. ISG15 binds the LFA-1 integrin receptor on NK- and T-cells to potentiate their production of IFN-II, which is essential for mycobacterial immunity.
=== Intracellular conjugate: ISGylation === In a ubiquitin-like fashion, ISG15 is covalently linked by its C-terminal LRLRGG motif to lysine residues on newly synthesized proteins.
ISG15, also known as Interferon-induced 15 kDa protein, Interferon-induced 17 kDa protein, or Ubiquitin cross-reactive protein, plays a crucial role in the innate immune response to viral infections. It functions either through conjugation to a target protein, a process known as ISGylation, or as a free, unconjugated protein. ISGylation is a cascade of enzymatic reactions involving E1, E2, and E3 enzymes, which catalyze the attachment of ISG15 to a lysine residue on the target protein. ISG15 targets various proteins, including IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B, and CHMP6. Notably, ISGylation of the viral sensor IFIH1/MDA5 promotes its oligomerization, activating innate immunity against a broad range of viruses, including coronaviruses, flaviviruses, and picornaviruses. ISG15 also interacts with other key proteins, such as EIF2AK2/PKR, RIGI, EIF4E2, UBE2N, UBE2E1, IRF3, and FLNB, influencing their functions in antiviral signaling. ISG15 exhibits antiviral activity against both DNA and RNA viruses, including influenza A, HIV-1, and Ebola virus. It restricts HIV-1 and Ebola virus by interfering with viral budding. Specifically, ISG15 inhibits the ubiquitination of HIV-1 Gag and host TSG101, disrupting their interaction and preventing the assembly and release of virions from infected cells. It also inhibits Ebola virus budding mediated by the VP40 protein by disrupting the ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISG15 targets influenza A virus NS1 protein, causing a loss of function in the protein and inhibiting viral replication. Additionally, the secreted form of ISG15 can induce natural killer cell proliferation, act as a chemotactic factor for neutrophils, and function as an IFN-gamma-inducing cytokine, playing a vital role in antimycobacterial immunity. It interacts with the integrin ITGAL/ITGB2 receptor, activating SRC family tyrosine kinases such as LYN, HCK, and FGR, leading to the secretion of IFNG and IL10. This interaction is mediated by ITGAL. ISG15 exists as a homodimer linked by disulfide bonds. It interacts with and is conjugated to its targets by UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme). ISG15 also interacts with NEDD4. Notably, ISG15 interacts with vaccinia virus protein E3. Furthermore, its interaction with influenza B NS1 protein inhibits ISG15 conjugation. ISG15 interacts with Crimean-Congo hemorrhagic fever virus (CCHFV) RNA-directed RNA polymerase L through its C-terminus, while the viral protein interacts through its N-terminus. The deISGylase activity of the viral protein disrupts antiviral signaling pathways mediated by NF-kappaB and IRF signaling. Lastly, ISG15 interacts with human cytomegalovirus protein UL26, inhibiting global protein ISGylation.
ISG15 is also known as G1P2, IFI15, IMD38, IP17, UCRP, hUCRP.
