Cells have quality-control mechanisms to recognize non-native protein structures and either help the proteins fold or promote their degradation. Ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) work together to assemble polyubiquitin chains on misfolded or misassembled proteins, which are then degraded by the proteasome. Here, we find that Ubc7, a yeast E2, can itself undergo degradation when its levels exceed that of its binding partner Cue1, a transmembrane protein that tethers Ubc7 to the endoplasmic reticulum. Unassembled, and thus mislocalized, Ubc7 is targeted to the proteasome by Ufd4, a homologous to E6-AP C-terminus (HECT)-class E3. Ubc7 is autoubiquitinated by a novel mechanism wherein the catalytic cysteine, instead of a lysine residue, provides the polyubiquitin chain acceptor site, and this cysteine-linked chain functions as a degradation signal. The polyubiquitin chain can also be transferred to a lysine side chain, suggesting a mechanism for polyubiquitin chain assembly that precedes substrate modification.
Bibliographical noteFunding Information:
We thank: Y. Reiss, G. Jona and O. Kerscher for valuable discussions; Y. Xie for providing the yeast deletion strain plate; Y. Xie, R. Hampton and T. Sommer for plasmids; and T. Biederer, R. Felberbaum, G. Jona and S. Kreft for comments on the manuscript. This work was supported by a U.S. National Institutes of Health (NIH) grant (GM046904) to M.H.