HOIL-1 ubiquitin ligase activity targets unbranched glucosaccharides and is required to prevent polyglucosan accumulation

Ian R. Kelsall (Lead / Corresponding author), Elisha H. McCrory, Yingqi Xu, Cheryl L. Scudamore, Sambit K. Nanda, Paula Mancebo-Gamella, Nicola T. Wood, Axel Knebel, Stephen J. Matthews, Philip Cohen (Lead / Corresponding author)

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30 Citations (Scopus)
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HOIL-1, a component of the linear ubiquitin chain assembly complex (LUBAC), ubiquitylates serine and threonine residues in proteins by esterification. Here, we report that mice expressing an E3 ligase-inactive HOIL-1[C458S] mutant accumulate polyglucosan in brain, heart and other organs, indicating that HOIL-1’s E3 ligase activity is essential to prevent these toxic polysaccharide deposits from accumulating. We found that HOIL-1 monoubiquitylates glycogen and α1:4-linked maltoheptaose in vitro and identify the C6 hydroxyl moiety of glucose as the site of ester-linked ubiquitylation. The monoubiquitylation of maltoheptaose was accelerated > 100-fold by the interaction of Met1-linked or Lys63-linked ubiquitin oligomers with the RBR domain of HOIL-1. HOIL-1 also transferred pre-formed ubiquitin oligomers to maltoheptaose en bloc, producing polyubiquitylated maltoheptaose in one catalytic step. The Sharpin and HOIP components of LUBAC, but not HOIL-1, bound to unbranched and infrequently branched glucose polymers in vitro, but not to highly branched mammalian glycogen, suggesting a potential function in targeting HOIL-1 to unbranched glucosaccharides in cells. We suggest that monoubiquitylation of unbranched glucosaccharides may initiate their removal from cells, preventing precipitation as polyglucosan.

Original languageEnglish
Article numbere109700
Pages (from-to)1-17
Number of pages17
JournalEMBO Journal
Issue number8
Early online date11 Mar 2022
Publication statusPublished - 19 Apr 2022


  • RBCK1
  • RBR E3 ligase
  • glycogen
  • polyglucosan
  • ubiquitination

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • General Biochemistry,Genetics and Molecular Biology
  • General Immunology and Microbiology


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