The human signal peptidase complex acts as a quality control enzyme for membrane proteins

Cells need to detect and degrade faulty membrane proteins to maintain homeostasis. In this study, we identify a previously unknown function of the human signal peptidase complex (SPC)—the enzyme that removes endoplasmic reticulum (ER) signal peptides—as a membrane protein quality control factor. We show that the SPC cleaves membrane proteins that fail to correctly fold or assemble into their native complexes at otherwise hidden cleavage sites, which our study reveals to be abundant in the human membrane proteome. This posttranslocational cleavage synergizes with ER-associated degradation to sustain membrane protein homeostasis and contributes to cellular fitness. Cryptic SPC cleavage sites thus serve as predetermined breaking points that, when exposed, help to target misfolded or surplus proteins for degradation, thereby maintaining a healthy membrane proteome. Description Weeding out faulty membrane proteins Membrane proteins connect the cell to its environment and are essential for key biological activities and cell survival. To function properly, membrane proteins need to adopt a well-defined three-dimensional structure within the lipid bilayer. Failures in this process give rise to numerous diseases. Zanotti et al. found that the human signal peptidase complex, which removes signal peptides from endoplasmic reticulum–targeted secretory and membrane proteins, has an additional quality control function. The complex cleaves faulty membrane proteins, supporting their degradation and helping to maintain a healthy membrane proteome. These findings extend our understanding of molecular quality control in cells and suggest potential targets in protein-folding disorders. —SMH The endoplasmic reticulum signal peptidase complex cleaves faulty membrane proteins to maintain cellular protein homeostasis.