Cellular targets and lysine selectivity of the HERC5 ISG15 ligase

Xu Zhao, Jessica M. Perez, Peter A. Faull, Catherine Chan, Femke W. Munting, Larissa A. Canadeo, Can Cenik, Jon M. Huibregtse*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


ISG15 is a type I interferon-induced ubiquitin-like modifier that functions in innate immune responses. The major human ISG15 ligase is hHERC5, a ribosome-associated HECT E3 that broadly ISGylates proteins cotranslationally. Here, we characterized the hHERC5-dependent ISGylome and identified over 2,000 modified lysines in over 1,100 proteins in IFN-β-stimulated cells. In parallel, we compared the substrate selectivity hHERC5 to the major mouse ISG15 ligase, mHERC6, and analysis of sequences surrounding ISGylation sites revealed that hHERC5 and mHERC6 have distinct preferences for amino acid sequence context. Several features of the datasets were consistent with ISGylation of ribosome-tethered nascent chains, and mHERC6, like hHERC5, cotranslationally modified nascent polypeptides. The ISGylome datasets presented here represent the largest numbers of protein targets and modification sites attributable to a single Ub/Ubl ligase and the lysine selectivities of the hHERC5 and mHERC6 enzymes may have implications for the activities of HECT domain ligases, generally.

Original languageEnglish (US)
Article number108820
Issue number2
StatePublished - Feb 16 2024


  • Biochemistry
  • Immunology
  • Molecular biology
  • Transcriptomics

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Cellular targets and lysine selectivity of the HERC5 ISG15 ligase'. Together they form a unique fingerprint.

Cite this