Invited Lecture
The Protease Ste24 Clears Clogged Translocons

Translocation into the endoplasmic reticulum (ER) is the first step in the biogenesis of thousands of eukaryotic endomembrane proteins. While functional ER translocation has been avidly studied, little is known about the mechanisms that resolve faulty states such as clogging, in which the substrate fails to properly translocate and obstructs the translocon pore. To shed light on the machinery required to resolve such faulty translocation scenarios, we carried out a systematic screen in Saccharomyces cerevisiae that highlighted a role for the ER metalloprotease Ste24. We demonstrate that Ste24 approaches the translocon upon clogging. There, Ste24 interacts with and generates fragments of the clogged nascent protein. Importantly, these functions are conserved in the human homologue, ZMPSTE24, while disease-associated forms of ZMPSTE24 are defective in clearing translocon clogging. These results shed light on an additional and critical task of Ste24, which serves to safe-guard the essential process of translocation.