Biology subjects

Goder, V.

Publications and source records attributed to Goder, V..

4 recordsLinked to original sources

bioRxiv2025

The lectin Emp47/ERGIC-53 targets misfolded O-mannosylated ER proteins to ERAD

The yeast bifunctional O-mannosyltransferase complex Pbn1-Gpi14 generates endoplasmic reticulum (ER)-associated degradation (ERAD) signals by O-mannosylating misfolded ER proteins, but how these signals are recognized is unknown. To address this question, we identified the binding partners of Pbn1 and found that the ER lectins Emp47 (ERGIC-53 in mammals) and Emp46 were among the strongest interactors. Simultaneous deletion of Emp46 and Emp47, but not of Yos9, impaired ERAD of an O-mannosylated, N-glycan-deficient CPY* variant. ERAD was restored by plasmid-expressed Emp47, but not by a mutant lacking its carbohydrate-recognition domain (CRD). Furthermore, we show that Emp47 interacts physically with the Hrd1 complex. Together, our data support a model in which Emp47 both recognizes O-mannoses on misfolded proteins and targets them to ERAD.

cell biology↗

bioRxiv2025

ER-associated degradation relying on protein O-mannosylation

Protein quality control in the secretory pathway, whose dysfunction is linked to various human diseases, begins in the endoplasmic reticulum (ER) and involves ER-associated degradation (ERAD) of terminally misfolded species. We have addressed the roles of protein O-mannosylation in ERAD using complementary genome-wide screens in yeast. Our findings reveal that protein O-mannosylation by the conserved ER-resident O-mannosyltransferase complex Pbn1-Gpi14 generates ERAD cues. This mechanism participates in regulating ERAD of substrates that contain serine-rich regions and provides a fail-safe mechanism for the degradation of non-N-glycosylated misfolded proteins. Our data suggest that the de novo synthesis of ERAD cues through protein O-mannosylation is an essential component of ER quality control.

cell biology↗

bioRxiv2019

A post-ER degradation pathway that relies on protease-dependent internalization from the vacuolar membrane

Newly synthesized proteins of the secretory pathway are quality-controlled inside the endoplasmic reticulum (ER) and, if not properly folded, are retained. An exception are glycosylphosphatidylinositol-anchored proteins (GPI-APs) which can leave the ER even when misfolded and are routed to the vacuole/lysosome for degradation by largely unknown mechanisms linked to post-ER quality control. Using yeast as model organism, we show that Gas1*, an ER-exported misfolded GPI-AP, is diverted from the secretory pathway to endosomes for transport to the vacuole. However, Gas1* is not sorted into endosomal intraluminal vesicles but internalizes directly from the vacuolar membrane. There, the vacuolar protease Pep4, but not any other known vacuolar protease, is required for Gas1* internalization. Our data reveal novel and unexpected mechanisms for invaginations from the vacuolar membrane.\n\nHighlightsO_LIER-exited misfolded GPI-anchored proteins are routed to the vacuole via endosomes but do not internalize into intraluminal vesicles\nC_LIO_LIInternalization occurs directly from the vacuolar membrane into intravacuolar mobile structures\nC_LIO_LIInternalization from the vacuolar membrane depends on the proteolytic activity of the vacuolar protease Pep4\nC_LI

cell biology↗

bioRxiv2018

Loss of glutathione redox homeostasis impairs proteostasis by inhibiting autophagy-dependent protein degradation

In the presence of aggregation-prone proteins, the cytosol and endoplasmic reticulum (ER) undergo a dramatic shift in their respective redox status, with the cytosol becoming more oxidized and the ER more reducing. However, whether and how changes in the cellular redox status may affect protein aggregation is unknown. Here, we show that C. elegans mutants lacking glutathione reductase gsr-1 gene enhance the deleterious phenotypes of heterologous human as well as endogenous worm aggregation-prone proteins. These effects are phenocopied by the GSH depleting agent diethyl maleate. Additionally, gsr-1 mutants abolish the nuclear translocation of HLH-30/TFEB transcription factor, a key inducer of autophagy, and strongly impair the degradation of the autophagy substrate p62/SQST-1::GFP, revealing glutathione reductase may have a role in the clearance of protein aggregates by autophagy. Blocking autophagy in gsr-1 worms expressing aggregation-prone proteins results in strong synthetic developmental phenotypes and lethality, supporting the physiological importance of glutathione reductase in the regulation of misfolded protein clearance. Furthermore, impairing redox homeostasis in both yeast and mammalian cells induces toxicity phenotypes associated with protein aggregation. Together, our data reveal that glutathione redox homeostasis may be central to proteostasis maintenance through autophagy regulation.

genetics↗