Abstract
Proteins are typically targeted for proteasomal degradation by the attachment of a polyubiquitin chain to ϵ-amino groups of lysine residues. Non-lysine ubiquitylation of proteasomal substrates has been considered an atypical and rare event limited to complex eukaryotes. Here we report that a fully functional lysine-less mutant of an inner nuclear membrane protein in yeast, Asi2, is polyubiquitylated and targeted for proteasomal degradation. Efficient degradation of lysine-free Asi2 requires E3-ligase Doa10 and E2 enzymes Ubc6 and Ubc7, components of the endoplasmic reticulum-associated degradation pathway. Together, our data suggest that non-lysine ubiquitylation may be more prevalent than currently considered.
Highlights
Atypical degradative polyubiquitylation on non-lysine residues has only been reported in metazoans
Lysine-less Asi2 Is Degraded via Ubiquitin-Proteasome Pathway—We have recently shown that inner nuclear membrane protein Asi2 is turned over in the nucleus by the ubiquitin-proteasome system involving E3 ligase Doa10 and E2 enzymes Ubc6 and Ubc7 [16]
We report ubiquitylation and proteasomal targeting of a lysine-less mutant Asi2
Summary
Atypical degradative polyubiquitylation on non-lysine residues has only been reported in metazoans. We report that a fully functional lysine-less mutant of an inner nuclear membrane protein in yeast, Asi, is polyubiquitylated and targeted for proteasomal degradation. Ubiquitylation at alternative acceptor sites has been observed in rare cases, including the attachment of ubiquitin to a substrate cysteine sulfhydryl group via thioester bond (4 – 6), to serine and threonine hydroxyl groups via ester bond [7,8,9,10], and to the N termini of proteins [11] It is unclear how frequently such noncanonical ubiquitylation is employed as a targeting signal for protein degradation. We report that a fully functional lysine-less mutant of yeast protein Asi is ubiquitylated on unconventional acceptor sites and targeted for proteasomal degradation in a Doa10-Ubc6-Ubc7-dependent manner. The finding that non-lysine ubiquitylation in yeast can target proteins for proteasomal degradation opens up enhanced opportunities to examine the biological significance of noncanonical ubiquitylation
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