Nuclear quality control of non-imported secretory proteins attenuates proteostasis decline in the cytosol
Banik, P.; Kamps, J.; Chen, Q.-Y.; Luesch, H.; Winklhofer, K. F.; Tatzelt, J.
Show abstract
Mistargeting of secretory proteins to the cytosol can induce formation of aggregation-prone conformers and subsequent proteostasis decline. We have identified a quality control pathway that redirects non-ER-imported prion protein (PrP) to proteasomal degradation in the nucleus to prevent formation of toxic aggregates in the cytosol. Upon aborted ER import, PrP sequentially interacted with VCP/p97 and importins, which kept PrP soluble and promoted its nuclear import. In the nucleus, RNA buffered aggregation of PrP to facilitate ubiquitin-dependent proteasomal degradation. Notably, the cytosolic interaction of PrP with VCP/p97 and its nuclear import were independent of ubiquitination but required the intrinsically unstructured N-terminal domain of PrP. Transient proteotoxic stress promoted the formation of self-perpetuating PrP aggregates in the cytosol, which disrupted further nuclear targeting of PrP and compromised cellular proteostasis. Our study delineates a VCP/p97-dependent nucleus-based quality control pathway of non-ER-imported secretory proteins and emphasizes the important role of the nuclear milieu for the degradation of aggregation-prone proteins.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
Similar papers in this journal
- Small disulfide loops in peptide hormones mediate self-aggregation and secretory granule sorting 95%
- ERLIN1/2 scaffolds bridge TMUB1 and RNF170 and restrict cholesterol esterification to regulate the secretory pathway 95%
- SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology 95%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.