{"doi":"10.1016/j.jbc.2025.110226","title":"Inactivation of SIAH-1 E3 ligase attenuates Aβ toxicity by suppressing ubiquitin-dependent DVE-1 degradation in Caenorhabditis elegans models of Alzheimer’s disease","abstract":"The mitochondrial unfolded protein response (UPR mt ), an evolutionarily conserved proteostasis pathway, plays a critical role in the pathogenesis of Alzheimer's disease (AD), characterized by amyloid-β peptide (Aβ) aggregation. Although the transcription factor DVE-1 regulates UPR mt activation in C. elegans and has been implicated in Aβ pathology, its regulatory mechanisms under AD-like conditions remain unclear. Here, using the classical C. elegans muscle-specific AD model (CL2006 strain), we observed UPR mt induction in young adults despite paradoxical depletion of DVE-1 protein concurrent with elevated dve-1 transcript levels. Through integrated genetic and biochemical analyses, we identified SIAH-1, a conserved E3 ubiquitin ligase that partners with the E2 enzyme UBC-25 to interact with DVE-1 and mediate its K48-linked polyubiquitination, as targeting DVE-1 for proteasomal degradation. Disruption of SIAH-1 E3 ubiquitin ligase function or overexpression of DVE-1 significantly reduced Aβ toxicity in both the muscle-expressed Aβ (CL2006) and neuronal Aβ models (gnaIs2) . These interventions concurrently suppressed Aβ aggregation in the heat shock-inducible Aβ aggregation model (xchIs15). Mechanistically, this protective effect was associated with restored mitochondrial homeostasis, as evidenced by MitoTracker Red staining and TOMM-20::mCherry fluorescence imaging in muscle-expressed Aβ animals. These assays demonstrated that Aβ accumulation compromises mitochondrial integrity, a phenotype markedly rescued in siah-1 deletion mutants and DVE-1-overexpressing strains. Collectively, these findings establish the SIAH-1/DVE-1 axis as a conserved proteostasis regulator and highlight ubiquitin-dependent mitochondrial quality control as a potential therapeutic target for AD and related proteopathies.","journal":"Journal of Biological Chemistry","year":2025,"id":528209,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1393028,"name":"Jiahui Liu","orcid":"0009-0006-6421-7833","position":1,"is_corresponding":false},{"id":1406209,"name":"Mingxia Lu","orcid":"0000-0003-3963-0408","position":2,"is_corresponding":false},{"id":1406210,"name":"Yingying Zhou","orcid":"0000-0002-9768-6066","position":3,"is_corresponding":false},{"id":1406567,"name":"Shuqi Guo","orcid":null,"position":4,"is_corresponding":false},{"id":1406568,"name":"Zhipeng Qin","orcid":null,"position":5,"is_corresponding":false},{"id":756925,"name":"Zekun Wang","orcid":"0000-0003-1962-9207","position":6,"is_corresponding":false},{"id":16728,"name":"Xiaojuan Sun","orcid":"0000-0003-3668-7628","position":7,"is_corresponding":false},{"id":1406208,"name":"Lihua Sun","orcid":"0000-0002-0888-7991","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:50:48.492873Z","pmid":"40349774","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":[]}