ER-assoziierte Proteindegradation (ERAD): die Erkennungs-, Retro-Translokations- und Abbaumaschinerie fehlgefalteter Proteine des ER
Zellbiologie
Zusammenfassung der Projektergebnisse
Biogenesis of membrane proteins, representing about 30% of the human proteome, mainly occurs within the Endoplasmic reticulum (ER). Maintenance of protein homeostasis is fundamentally important to match the cellular needs and to counteract stress conditions. Misfolded, misassembled or mistargeted proteins represent a high risk to cells, and deregulation of protein homeostasis mechanisms is linked to severe pathologies including diabetes and neurodegeneration. Therefore, the ER-associated degradation (ERAD) pathway performs an essential role to restore ER homeostasis under steady state and cellular stress conditions. ER resident, membrane-embedded E3 ubiquitin ligases serve as organizational centres for distinct protein complexes and collectively provide the essential substrate ubiquitination activity for degradation of ERAD substrates by the proteasome. Recent high-resolution structures revealed that the E3 ligase Hrd1 and the rhomboid pseudoprotease Der1 provide a sizable pore for the dislocation of luminal proteins into the cytoplasm. Despite years of genetic and biochemical work, still much less is known of how membrane proteins are extracted from the lipid bilayer in order to reach the cytoplasmic proteasome for degradation. Previous work from us as well as others groups, using budding yeast as a model system, showed that the rhomboid pseudoprotease Dfm1 is a crucial ERAD factor forming a putative extraction platform for membrane proteins, as well as chaperone-like activity and ERAD independent role in sphingolipid homeostasis. With this project, we aimed to define the precise physiological role of Dfm1 in S. cerevisiae, identify endogenous substrates, and decipher the molecular mechanism of membrane protein degradation in the ER, potentially linking ERAD (proteasomal degradation) and ER-phagy (lysosomal degradation).
Projektbezogene Publikationen (Auswahl)
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Mechanisms and physiological functions of ER-phagy. Curr Opin Physiol. 30:100613
Sanz-Martinez P, Stolz A.
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Live-Cell High-Throughput Screen for Monitoring Autophagy Flux. Methods in Molecular Biology (2023), 215-224. Springer US.
Cano-Franco, Sara; Ho-Xuan, Hung; Brunello, Lorene & Stolz, Alexandra
