ISG15 conjugation : cellular targets and the lysine selectivity of HERC5
type: CreativeWork
description: ISG15 is a 17 kDa ubiquitin-like protein that functions in the innate immune response to pathogens. While human ISG15 is a multifunctional protein, its canonical function is that of an intracellular ubiquitin-like protein modifier. Like ISG15, the human E1 (UBE1L), E2 (UBE2L6) and E3 (HERC5) enzymes for ISG15 are all induced at the transcriptional level by type I IFN. ISGylation of pathogen and host proteins is a component of cellular defense against viruses. Consistent with this, many viruses have evolved mechanisms to counteract the effects of ISGylation. SARS-CoV-2, for example, encodes an ISG15-deconjugating activity (PLpro) that reverses ISGylation. Similarly, foot and mouth disease virus (FMDV) expresses a protease that not only deconjugates ISG15 but renders it incapable of being re-conjugated, while the Influenza B NS1 protein binds and sequesters ISGylated proteins to block the anti-viral effect of ISG15 conjugation. HERC5 is the major ISG15 ligase in humans and targets hundreds of cellular and viral proteins for ISGylation. HERC5 associates with polysomes and appears to target nascent polypeptides in a near stochastic manner, with limited substrate selectivity. A model for HERC5 function is that, in the context of a type I interferon response, newly translated viral proteins are the biologically relevant targets of ISGylation. This would be expected to exert selective pressure on the evolution of viral protein sequences, which in turn would influence the evolution of HERC5 target protein and lysine selectivity. Consistent with a host-pathogen “arms race”, HERC5 been shown to be under positive selection. Here, I have used DiGly proteomics, a bottom-up proteomics methodology that employs a general motif antibody to enrich ISGylation site-containing peptides, to characterize HERC5 activities and specificities with respect to residues flanking modified lysines, local physiochemical and structural properties of modified sites and exploring the possible biologic…
abstract: ISG15 is a 17 kDa ubiquitin-like protein that functions in the innate immune response to pathogens. While human ISG15 is a multifunctional protein, its canonical function is that of an intracellular ubiquitin-like protein modifier. Like ISG15, the human E1 (UBE1L), E2 (UBE2L6) and E3 (HERC5) enzymes for ISG15 are all induced at the transcriptional level by type I IFN. ISGylation of pathogen and host proteins is a component of cellular defense against viruses. Consistent with this, many viruses have evolved mechanisms to counteract the effects of ISGylation. SARS-CoV-2, for example, encodes an ISG15-deconjugating activity (PLpro) that reverses ISGylation. Similarly, foot and mouth disease virus (FMDV) expresses a protease that not only deconjugates ISG15 but renders it incapable of being re-conjugated, while the Influenza B NS1 protein binds and sequesters ISGylated proteins to block the anti-viral effect of ISG15 conjugation. HERC5 is the major ISG15 ligase in humans and targets hundreds of cellular and viral proteins for ISGylation. HERC5 associates with polysomes and appears to target nascent polypeptides in a near stochastic manner, with limited substrate selectivity. A model for HERC5 function is that, in the context of a type I interferon response, newly translated viral proteins are the biologically relevant targets of ISGylation. This would be expected to exert selective pressure on the evolution of viral protein sequences, which in turn would influence the evolution of HERC5 target protein and lysine selectivity. Consistent with a host-pathogen “arms race”, HERC5 been shown to be under positive selection. Here, I have used DiGly proteomics, a bottom-up proteomics methodology that employs a general motif antibody to enrich ISGylation site-containing peptides, to characterize HERC5 activities and specificities with respect to residues flanking modified lysines, local physiochemical and structural properties of modified sites and exploring the possible biologic…
author: Zhao, Xu, Ph. D.
keywords: DiGly proteomic, Sequence preference, Human HERC5, Mouse HERC6, Cotranslational, ISG15, Conjugation
date published: 2023-05
date modified: 2026-07-24T05:01:06Z
provider: University of Texas
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: The University of Texas at Austin

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2152/131950

PropertyValue
property ID: DOI
value: 10.26153/tsw/59294