Reactome | ISG15 antiviral mechanism

ISG15 antiviral mechanism

Stable Identifier

R-HSA-1169408

Type

Pathway

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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Interferon-stimulated gene 15 (ISG15) is a member of the ubiquitin-like (Ubl) family. It is strongly induced upon exposure to type I Interferons (IFNs), viruses, bacterial LPS, and other stresses. Once released the mature ISG15 conjugates with an array of target proteins, a process termed ISGylation. ISGylation utilizes a mechanism similar to ubiquitination, requiring a three-step enzymatic cascade. UBE1L is the ISG15 E1 activating enzyme which specifically activates ISG15 at the expense of ATP. ISG15 is then transfered from E1 to the E2 conjugating enzyme UBCH8 and then to the target protein with the aid of an ISG15 E3 ligase, such as HERC5 and EFP. Hundreds of target proteins for ISGylation have been identified. Several proteins that are part of antiviral signaling pathways, such as RIG-I, MDA5, Mx1, PKR, filamin B, STAT1, IRF3 and JAK1, have been identified as targets for ISGylation. ISG15 also conjugates some viral proteins, inhibiting viral budding and release. ISGylation appears to act either by disrupting the activity of a target protein and/or by altering its localization within the cell.

Literature References

PubMed ID	Title	Journal	Year
12582176	High-throughput immunoblotting. Ubiquitiin-like protein ISG15 modifies key regulators of signal transduction Malakhova, OA, Malakhov, MP, Zhang, DE, Jacobs, BS, Borden, EC, Kim, KI	J Biol Chem	2003
15970528	ISG15: a ubiquitin-like enigma Zhang, DE, Dao, CT	Front Biosci	2005
20153823	ISG15 and immune diseases Jeon, YJ, Yoo, HM, Chung, CH	Biochim Biophys Acta	2010
	Antiviral Properties of ISG15 Lenschow, DJ
16009940	Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways Denison, C, Krug, RM, Huibregtse, JM, Gygi, S, Zhao, C	Proc Natl Acad Sci U S A	2005
20946978	Emerging role of ISG15 in antiviral immunity Chen, ZJ, Skaug, B	Cell	2010