Linear ubiquitination in immunity

Immunol Rev. 2015 Jul;266(1):190-207. doi: 10.1111/imr.12309.


Linear ubiquitination is a post-translational protein modification recently discovered to be crucial for innate and adaptive immune signaling. The function of linear ubiquitin chains is regulated at multiple levels: generation, recognition, and removal. These chains are generated by the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin E3 capable of forming the linear ubiquitin linkage de novo. LUBAC is not only relevant for activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) in various signaling pathways, but importantly, it also regulates cell death downstream of immune receptors capable of inducing this response. Recognition of the linear ubiquitin linkage is specifically mediated by certain ubiquitin receptors, which is crucial for translation into the intended signaling outputs. LUBAC deficiency results in attenuated gene activation and increased cell death, causing pathologic conditions in both, mice, and humans. Removal of ubiquitin chains is mediated by deubiquitinases (DUBs). Two of them, OTULIN and CYLD, are constitutively associated with LUBAC. Here, we review the current knowledge on linear ubiquitination in immune signaling pathways and the biochemical mechanisms as to how linear polyubiquitin exerts its functions distinctly from those of other ubiquitin linkage types.

Keywords: cell death; deubiquitinases; inflammation; linear ubiquitination; signaling pathways.

Publication types

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

MeSH terms

  • Animals
  • Cell Death
  • Deubiquitinating Enzyme CYLD
  • Endopeptidases / metabolism*
  • Humans
  • Immunity
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Multiprotein Complexes
  • NF-kappa B / metabolism
  • Protein Processing, Post-Translational
  • Signal Transduction
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitination


  • Multiprotein Complexes
  • NF-kappa B
  • Tumor Suppressor Proteins
  • Mitogen-Activated Protein Kinase Kinases
  • Endopeptidases
  • OTULIN protein, human
  • CYLD protein, human
  • Deubiquitinating Enzyme CYLD