The Met1-Linked Ubiquitin Machinery: Emerging Themes of (De)regulation

Mol Cell. 2017 Oct 19;68(2):265-280. doi: 10.1016/j.molcel.2017.09.001.


The linear ubiquitin chain assembly complex, LUBAC, is the only known mammalian ubiquitin ligase that makes methionine 1 (Met1)-linked polyubiquitin (also referred to as linear ubiquitin). A decade after LUBAC was discovered as a cellular activity of unknown function, there are now many lines of evidence connecting Met1-linked polyubiquitin to NF-κB signaling, cell death, inflammation, immunity, and cancer. We now know that Met1-linked polyubiquitin has potent signaling functions and that its deregulation is connected to disease. Indeed, mutations and deficiencies in several factors involved in conjugation and deconjugation of Met1-linked polyubiquitin have been implicated in immune-related disorders. Here, we discuss current knowledge and recent insights into the role and regulation of Met1-linked polyubiquitin, with an emphasis on the mechanisms controlling the function of LUBAC.

Keywords: CYLD; LUBAC; Met1-linked ubiquitin; OTULIN; SPATA2; cancer; caspases; host-pathogen interaction; immune disorders; linear ubiquitin.

Publication types

  • Review

MeSH terms

  • Animals
  • Cell Death
  • Humans
  • Immunity*
  • NF-kappa B / genetics
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Neoplasm Proteins / immunology
  • Neoplasm Proteins / metabolism*
  • Neoplasms / immunology
  • Neoplasms / metabolism*
  • Polyubiquitin / genetics
  • Polyubiquitin / immunology
  • Polyubiquitin / metabolism*
  • Signal Transduction*


  • NF-kappa B
  • Neoplasm Proteins
  • Polyubiquitin