Recombinant Mouse Ubiquitin-like protein ISG15 (Isg15)

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 SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, TRIM25, STAT5A, MAPK1/ERK2 and globin. 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: RIGI which inhibits its function in antiviral signaling response, IRF3 which inhibits its ubiquitination and degradation as well as EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A and B virus, sindbis virus (SV) and herpes simplex type-1 (HHV-1). Plays a significant role in the control of neonatal Chikungunya virus (CHIKV) infection by acting as a putative immunomodulator of pro-inflammatory cytokines. Protects mice against the consequences of Chikungunya virus infection by down-regulating the pathogenic cytokine response, often denoted as the cytokine storm. Plays a role in erythroid differentiation. 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 (By similarity)

Subcellular Location

Cytoplasm; Secreted

Subunit

Homodimer; disulfide-linked (By similarity). Interacts with, and is conjugated to its targets by the UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) (By similarity). Interacts with NEDD4 (By similarity). Interacts with PARP12; this interaction inhibits PINK1/Parkin-dependent mitophagy (By similarity)

• Fahey D. et al. Nucleotide sequence and deduced amino acid sequence of a cDNA encoding an interferon-induced mouse 15-KDa protein. (OCT-)
• Garlie N.K. et al. Sequence differences between murine ISG15, human ISG15 and ubiquitin: a functional divergence from ubiquitin. (JUN-)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Hamerman J.A. et al. Serpin 2a is induced in activated macrophages and conjugates to a ubiquitin homolog. — J. Immunol. (2002)
• Owhashi M. et al. Identification of a ubiquitin family protein as a novel neutrophil chemotactic factor. — Biochem. Biophys. Res. Commun. (2003)
• Malakhov M.P. et al. High-throughput immunoblotting. Ubiquitin-like protein ISG15 modifies key regulators of signal transduction. — J. Biol. Chem. (2003)
• Lenschow D.J. et al. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. — J. Virol. (2005)
• Zou W. et al. Negative regulation of ISG15 E3 ligase EFP through its autoISGylation. — Biochem. Biophys. Res. Commun. (2007)