The multifaceted role of the E3 ubiquitin ligase HOIL-1: beyond linear ubiquitination

Immunol Rev. 2015 Jul;266(1):208-21. doi: 10.1111/imr.12307.


Ubiquitination controls and fine-tunes many signaling processes driving immunity, inflammation, and cancer. The E3 ubiquitin ligase HOIL-1 (heme-oxidized IRP2 ubiquitin ligase-1) is increasingly implicated in different signaling pathways and plays a vital role in immune regulation. HOIL-1 co operates with the E3 ubiquitin ligase HOIP (HOIL-1 interacting protein) to modify specific nuclear factor-κB (NF-κB) signaling proteins with linear M1-linked polyubiquitin chains. In addition, through its ability to also add K48-linked polyubiquitin chains to specific substrates, HOIL-1 has been linked with antiviral signaling, iron and xenobiotic metabolism, cell death, and cancer. HOIL-1 deficiency in humans leads to myopathy, amylopectinosis, auto-inflammation, and immunodeficiency associated with an increased frequency of bacterial infections. HOIL-1-deficient mice exhibit amylopectin-like deposits in the myocardium, pathogen-specific immunodeficiency, but minimal signs of hyper-inflammation. This review summarizes current knowledge on the mechanism of action of HOIL-1 and highlights recent advances regarding its role in health and disease.

Keywords: HOIL-1; RBCK1; cancer; immunity; metabolism; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Immunologic Deficiency Syndromes / immunology*
  • Mice
  • NF-kappa B
  • Signal Transduction
  • Transcription Factors
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination


  • NF-kappa B
  • Transcription Factors
  • RBCK1 protein, human
  • Ubiquitin-Protein Ligases