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

Autor: Kelsall IR; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK., McCrory EH; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK., Xu Y; Cross-Faculty NMR Centre, Department of Life Sciences, Imperial College London, London, UK., Scudamore CL; Exepathology, Exeter, UK., Nanda SK; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK., Mancebo-Gamella P; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK., Wood NT; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK., Knebel A; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK., Matthews SJ; Cross-Faculty NMR Centre, Department of Life Sciences, Imperial College London, London, UK., Cohen P; MRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
Jazyk: angličtina
Zdroj: The EMBO journal [EMBO J] 2022 Apr 19; Vol. 41 (8), pp. e109700. Date of Electronic Publication: 2022 Mar 11.
DOI: 10.15252/embj.2021109700
Abstrakt: 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.
(©2022 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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