Identification of ERAD-dependent degrons for the endoplasmic reticulum lumen

Summary

Degrons are the minimal features that target proteins for degradation. In most cases, degrons allow recognition by components of the cytosolic ubiquitin proteasome system. Currently, every degron that has been identified only functions within the cytosol. Using Saccharomyces cerevisiae, we identified the first short linear sequences that function as degrons from the endoplasmic reticulum (ER) lumen. We show that when these degrons are transferred to proteins, they facilitate degradation through the ERAD system at the cytosolic proteasome. These degrons enable degradation of both luminal and integral membrane ER proteins, expanding the types of proteins that can be targeted for degradation both in budding yeast and in mammalian tissue culture. This discovery provides a framework to target proteins for degradation from the previously unreachable ER lumen and enables novel therapeutic approaches that exploit the highly-conserved ERAD system.