1 research outputs found
HOIL-1 ubiquitin ligase activity targets unbranched glucosaccharides and is required to prevent polyglucosan accumulation
HOILâ1, 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 ligaseâinactive HOILâ1[C458S] mutant accumulate polyglucosan in brain, heart and other organs, indicating that HOILâ1âs E3 ligase activity is essential to prevent these toxic polysaccharide deposits from accumulating. We found that HOILâ1 monoubiquitylates glycogen and α1:4âlinked maltoheptaose in vitro and identify the C6 hydroxyl moiety of glucose as the site of esterâlinked ubiquitylation. The monoubiquitylation of maltoheptaose was accelerated > 100âfold by the interaction of Met1âlinked or Lys63âlinked ubiquitin oligomers with the RBR domain of HOILâ1. HOILâ1 also transferred preâformed ubiquitin oligomers to maltoheptaose en bloc, producing polyubiquitylated maltoheptaose in one catalytic step. The Sharpin and HOIP components of LUBAC, but not HOILâ1, bound to unbranched and infrequently branched glucose polymers in vitro, but not to highly branched mammalian glycogen, suggesting a potential function in targeting HOILâ1 to unbranched glucosaccharides in cells. We suggest that monoubiquitylation of unbranched glucosaccharides may initiate their removal from cells, preventing precipitation as polyglucosan