Review Article

ISG15 in antiviral immunity and beyond



The host response to viral infection includes the induction of type I interferons and the subsequent upregulation of hundreds of interferon-stimulated genes. Ubiquitin-like protein ISG15 is an interferon-induced protein that has been implicated as a central player in the host antiviral response. Over the past 15 years, efforts to understand how ISG15 protects the host during infection have revealed that its actions are diverse and pathogen-dependent. In this Review, we describe new insights into how ISG15 directly inhibits viral replication and discuss the recent finding that ISG15 modulates the host damage and repair response, immune response and other host signalling pathways. We also explore the viral immune-evasion strategies that counteract the actions of ISG15. These findings are integrated with a discussion of the recent identification of ISG15-deficient individuals and a cellular receptor for ISG15 that provides new insights into how ISG15 shapes the host response to viral infection.

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The authors thank the members of the Lenschow laboratory for their critical reading of the manuscript during its preparation. The authors gratefully acknowledge support from the US National Institutes of Health (NIH) R01 AI080672 and Pew Charitable Trusts. Y.P. is funded through a Children Discovery Institute postdoctoral fellowship and the NIH postdoctoral training grant T32 CA009547.

Author information


  1. Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA

    • Yi-Chieh Perng
    •  & Deborah J. Lenschow
  2. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA

    • Deborah J. Lenschow


  1. Search for Yi-Chieh Perng in:

  2. Search for Deborah J. Lenschow in:


Y.P. researched data for the article. Y.P. and D.J.L. substantially contributed to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Deborah J. Lenschow.

Glossary terms


A small regulatory protein that can be added to a substrate protein by a process known as ubiquitylation and can alter the function of the substrate protein through degradation, localization and protein–protein interactions.

Ubiquitin-like modifiers

(Ubls). Small regulatory proteins that possess ubiquitin folds and are often conjugated onto a target protein similar to ubiquitin to alter function.

Genotoxic stressors

Agents that damage the genetic information within a cell, causing mutations or diseases.

Proteasome-mediated degradation

A cellular process to regulate the concentration of proteins and to degrade misfolded proteins by proteolysis, a chemical reaction that breaks peptide bonds.

Leader signal

A short peptide present at the amino terminus of newly synthesized proteins that are destined for the secretory pathway.

Secretory lysosomes

Dual-function organelles that could be used as a lysosome for degradation and hydrolysis and for storage of secretory proteins within the cell.


A double-stranded RNA helicase enzyme that functions as a cytosolic pattern-recognition receptor that recognizes short double-stranded or single-stranded RNA from viruses and triggers an antiviral response.

Usp18-knock-in mice

Mice in which the endogenous USP18 gene was replaced with a USP18 gene mutated so that it maintains its ability to bind to and inhibit signalling through the type I interferon receptor but its de-ISGylating capacity is lost, resulting in the accumulation of ISG15 conjugates.

Protein kinase R

(PKR). An interferon-induced, dsRNA-activated protein kinase that phosphorylates the eukaryotic translation initiation factor (eIF2α) in response to dsRNA and cellular stress, including viral infections.

Ovarian tumour domain

(OTU domain). A domain that is a shared protein region of a family of deubiquitylating proteolytic enzymes involved in processing of ubiquitin precursors.

Exosome secretion

A cellular secretion pathway mediated by the release of small membrane vesicles from multivesicular endosomes.

Viral latency

A type of persistent viral infection in which the pathogenic virus lies dormant without killing infected cells until it is reactivated by certain stimuli.

Aicardi–Goutières syndrome

(AGS). A rare, early-onset childhood inflammatory disorder characterized by elevated levels of type I interferons that results in skin and central nervous system manifestations.

Pathogen burden

The number of pathogens in an infected host that require the immune system for eradication.


An antiviral medication used to treat hepatitis C, respiratory syncytial virus and other viral infections.


A type of autophagy in which a defective and/or dysfunctional mitochondrion is selectively degraded by the lysosome.

Interferon-sensitive response element

(IRSE). A specific nucleotide sequence located in the promoters of interferon-stimulated genes (ISGs) that can bind to interferon stimulated gene factor 3 (ISGF3) or other transcriptional complexes upon type I interferon stimulation to initiation transcription of ISGs.