{"doi":"10.1101/2023.06.27.546668","title":"Nuclear quality control of non-imported secretory proteins attenuates proteostasis decline in the cytosol","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":409074,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1188518,"name":"Janine Kamps","orcid":"0000-0002-4930-3868","position":1,"is_corresponding":false},{"id":523148,"name":"Qi-Yin Chen","orcid":null,"position":2,"is_corresponding":false},{"id":271196,"name":"Hendrik Luesch","orcid":"0000-0002-4091-7492","position":3,"is_corresponding":false},{"id":583331,"name":"Konstanze F. Winklhofer","orcid":"0000-0002-7256-8231","position":4,"is_corresponding":false},{"id":592083,"name":"Jörg Tatzelt","orcid":"0000-0001-5017-5528","position":5,"is_corresponding":false},{"id":1188517,"name":"P. Banik","orcid":"0000-0002-5890-2141","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":null,"created_at":"2026-07-19T01:21:22.368387Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}