UniProt functional annotation for Q64339



	UniProt functional annotation for Q64339

UniProt code: Q64339.

Organism: Mus musculus (Mouse).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.

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. Can also isgylate: DDX58/RIG-I 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 proinflammatory cytokines. Protects mice against the consequences of Chikungunya virus infection by downregulating 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). {ECO:0000250|UniProtKB:P05161, ECO:0000269|PubMed:16254333, ECO:0000269|PubMed:17222803, ECO:0000269|PubMed:17227866, ECO:0000269|PubMed:17289916, ECO:0000269|PubMed:18057259, ECO:0000269|PubMed:22022510, ECO:0000269|PubMed:22028657, ECO:0000269|PubMed:22859821, ECO:0000269|PubMed:32726803}.

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). {ECO:0000250|UniProtKB:P05161}.

Subcellular location: Cytoplasm {ECO:0000250|UniProtKB:P05161}. Secreted {ECO:0000250|UniProtKB:P05161}. Note=Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins. {ECO:0000250|UniProtKB:P05161}.

Induction: By type I interferons.

Domain: Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are required for its efficient conjugation to cellular proteins. The two domains play different roles in the ISGylation pathway: Ubiquitin-like 2 domain is necessary for the first two steps allowing the linking of ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is essential for the final, E3-mediated transfer of ISG15, from the E2 to the Lys of the target protein. {ECO:0000250|UniProtKB:P05161}.

Ptm: S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins. {ECO:0000269|PubMed:18606809}.

Ptm: Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases (By similarity). {ECO:0000250|UniProtKB:P05161}.

Mass spectrometry: Mass=17015; Method=MALDI; Evidence={ECO:0000269|PubMed:12963022};

Annotations taken from UniProtKB at the EBI.


Organism:		Mus musculus (Mouse).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; Murinae; Mus; Mus.



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. Can also isgylate: DDX58/RIG-I 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 proinflammatory cytokines. Protects mice against the consequences of Chikungunya virus infection by downregulating 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). {ECO:0000250\|UniProtKB:P05161, ECO:0000269\|PubMed:16254333, ECO:0000269\|PubMed:17222803, ECO:0000269\|PubMed:17227866, ECO:0000269\|PubMed:17289916, ECO:0000269\|PubMed:18057259, ECO:0000269\|PubMed:22022510, ECO:0000269\|PubMed:22028657, ECO:0000269\|PubMed:22859821, ECO:0000269\|PubMed:32726803}.


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). {ECO:0000250\|UniProtKB:P05161}.
Subcellular location:		Cytoplasm {ECO:0000250\|UniProtKB:P05161}. Secreted {ECO:0000250\|UniProtKB:P05161}. Note=Exists in three distinct states: free within the cell, released into the extracellular space, or conjugated to target proteins. {ECO:0000250\|UniProtKB:P05161}.
Induction:		By type I interferons.
Domain:		Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are required for its efficient conjugation to cellular proteins. The two domains play different roles in the ISGylation pathway: Ubiquitin-like 2 domain is necessary for the first two steps allowing the linking of ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is essential for the final, E3-mediated transfer of ISG15, from the E2 to the Lys of the target protein. {ECO:0000250\|UniProtKB:P05161}.
Ptm:		S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins. {ECO:0000269\|PubMed:18606809}.
Ptm:		Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases (By similarity). {ECO:0000250\|UniProtKB:P05161}.
Mass spectrometry:		Mass=17015; Method=MALDI; Evidence={ECO:0000269\|PubMed:12963022};