{"doi":"10.1161/circresaha.119.316007","title":"The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction","abstract":"Rationale: The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime show cardiotoxicity. Moreover, UPS and autophagic-lysosomal pathway defects are implicated in cardiac pathogenesis. Hence, a better understanding of the cross-talk between the 2 catabolic pathways will help advance cardiac pathophysiology and medicine. Objective: Systemic proteasome inhibition (PSMI) was shown to increase p62/SQSTM1 expression and induce myocardial macroautophagy. Here we investigate how proteasome malfunction activates cardiac autophagic-lysosomal pathway. Methods and Results: Myocardial macroautophagy, TFEB (transcription factor EB) expression and activity, and p62 expression were markedly increased in mice with either cardiomyocyte-restricted ablation of Psmc1 (an essential proteasome subunit gene) or pharmacological PSMI. In cultured cardiomyocytes, PSMI-induced increases in TFEB activation and p62 expression were blunted by pharmacological and genetic calcineurin inhibition and by siRNA-mediated Molcn1 silencing. PSMI induced remarkable increases in myocardial autophagic flux in wild type mice but not p62 null (p62-KO) mice. Bortezomib-induced left ventricular wall thickening and diastolic malfunction was exacerbated by p62 deficiency. In cultured cardiomyocytes from wild type mice but not p62-KO mice, PSMI induced increases in LC3-II flux and the lysosomal removal of ubiquitinated proteins. Myocardial TFEB activation by PSMI as reflected by TFEB nuclear localization and target gene expression was strikingly less in p62-KO mice compared with wild type mice. Conclusions: (1) The activation of cardiac macroautophagy by proteasomal malfunction is mediated by the Mocln1-calcineurin-TFEB-p62 pathway; (2) p62 unexpectedly exerts a feed-forward effect on TFEB activation by proteasome malfunction; and (3) targeting the Mcoln1 (mucolipin1)-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac autophagic-lysosomal pathway activation during proteasome malfunction.","journal":"Circulation Research","year":2020,"id":52283,"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":137,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":263763,"name":"Jie Li","orcid":"0000-0003-3902-642X","position":1,"is_corresponding":false},{"id":263764,"name":"Nirmal Parajuli","orcid":"0000-0002-0799-6301","position":2,"is_corresponding":false},{"id":265390,"name":"Zongwen Tian","orcid":null,"position":3,"is_corresponding":false},{"id":265391,"name":"Penglong Wu","orcid":null,"position":4,"is_corresponding":false},{"id":263765,"name":"Megan T. Lewno","orcid":"0000-0003-4824-4779","position":5,"is_corresponding":false},{"id":263766,"name":"Jianqiu Zou","orcid":"0000-0003-4199-9212","position":6,"is_corresponding":false},{"id":263767,"name":"Wenjuan Wang","orcid":"0000-0002-1879-7332","position":7,"is_corresponding":false},{"id":142460,"name":"Lynn Bedford","orcid":null,"position":8,"is_corresponding":false},{"id":142465,"name":"R. John Mayer","orcid":null,"position":9,"is_corresponding":false},{"id":263768,"name":"Jing Fang","orcid":"0000-0002-4950-626X","position":10,"is_corresponding":false},{"id":263769,"name":"Jinbao Liu","orcid":"0000-0002-5640-0930","position":11,"is_corresponding":false},{"id":263770,"name":"Taixing Cui","orcid":"0000-0002-9528-7299","position":12,"is_corresponding":false},{"id":263771,"name":"Huabo Su","orcid":"0000-0002-8475-2685","position":13,"is_corresponding":false},{"id":263772,"name":"Xuejun Wang","orcid":"0000-0001-9267-1343","position":14,"is_corresponding":false},{"id":263762,"name":"Bo Pan","orcid":"0000-0002-5705-5446","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-18T20:42:26.843314Z","pmid":"32366200","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":[]}