Membrane proteins make up one quarter of the entire human proteome. Misfolded membrane proteins are generally retained in the ER and rapidly degraded. Cells thus have evolved means to specifically detect and handle thousands of different aberrant membrane proteins. As opposed to our comprehensive understanding of ER chaperones for soluble proteins, our insights into dedicated membrane protein chaperones remain limited. We thus use systematic approaches to define novel membrane protein chaperones and quality control factors and analyze their mechanisms of action and biological functions. We focus on disease-causing membrane proteins as models, as defining novel chaperone machineries for those may have an immediate impact on the future of diagnosing and treating human disorders caused by membrane protein folding defects.

As an example, we could show that the signal peptidase complex, the defining enzyme of the signal hypothesis for ER-targeted proteins, has an additional quality control function for membrane proteins. It cleaves those at sites that get buried upon folding, allowing for efficient and irreversible quality control steps when a membrane protein misfolds (Zanotti, Coelho et al., 2022, Science [read]).