The Proteasome Distinguishes between Heterotypic and Homotypic Lysine-11-Linked Polyubiquitin Chains

Proteasome-mediated degradation occurs with proteins principally modified with lysine-48 polyubiquitin chains. Whether the proteasome also can bind atypical ubiquitin chains, including those linked by lysine-11, has not been well established. This is critically important, as lysine-11 polyubiquitination has been implicated in both proteasome-mediated degradation and non-degradative outcomes. Here we demonstrate that pure homotypic lysine-11-linked chains do not bind strongly to the mammalian proteasome. By contrast, heterotypic polyubiquitin chains, containing lysine-11 and lysine-48 linkages, not only bind to the proteasome but also stimulate the proteasomal degradation of the cell-cycle regulator cyclin B1. Thus, while heterotypic lysine-11-linked chains facilitate proteasomal degradation, homotypic lysine-11 linkages adopt conformations that prevent association with the proteasome. Our data demonstrate the capacity of the proteasome to bind ubiquitin chains of distinct topology, with implications for the recognition and diverse biological functions of mixed ubiquitin chains. [Display omitted] •Homotypic K11-polyubiquitin chains do not bind strongly to the proteasome•Proteasome shuttling factors preferentially bind K48 chains compared to K11 chains•Heterotypic but not homotypic K11 chains stimulate proteasomal degradation•The proteasome disassembles both homotypic and heterotypic K11-polyubiquitin chains It is unclear whether atypical polyubiquitin chains signal proteasomal degradation. Grice et al. show that, while heterotypic lysine-11-linked polyubiquitin chains bind to the proteasome and stimulate degradation of cyclin B1, proteins modified with homotypic lysine-11-linked chains neither bind strongly to proteasomes nor signal efficient degradation.