The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction

Pan, Bo; Li, Jie; Parajuli, Nirmal; Tian, Zongwen; Wu, Penglong; Lewno, Megan T; Zou, Jianqiu; Wang, Wenjuan; Bedford, Lynn; Mayer, Roland John; Fang, Jing; Liu, Jinbao; Cui, Taixing; Su, Huabo; Wang, Xuejun

Abstract

Rationale: The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway (ALP) 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 ALP defects are implicated in cardiac pathogenesis. Hence, a better understanding of the cross-talk between the two 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 ALP.

Methods and Results: Myocardial macroautophagy, transcription factor EB (TFEB) 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 (WT) 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 WT 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 WT 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-calcineurin-TFEB-p62 pathway may provide new means to intervene cardiac ALP activation during proteasome malfunction.

Citation

Pan, B., Li, J., Parajuli, N., Tian, Z., Wu, P., Lewno, M. T., Zou, J., Wang, W., Bedford, L., Mayer, R. J., Fang, J., Liu, J., Cui, T., Su, H., & Wang, X. (2020). The Calcineurin-TFEB-p62 Pathway Mediates the Activation of Cardiac Macroautophagy by Proteasomal Malfunction. Circulation Research, 127(4), 502–518. https://doi.org/10.1161/circresaha.119.316007

• Journal Article Type: Article
• Acceptance Date: May 4, 2020
• Online Publication Date: May 5, 2020
• Publication Date: Jul 31, 2020
• Deposit Date: May 19, 2020
• Publicly Available Date: Nov 6, 2020
• Journal: Circulation Research
• Print ISSN: 0009-7330
• Electronic ISSN: 1524-4571
• Publisher: American Heart Association
• Peer Reviewed: Peer Reviewed
• Volume: 127
• Issue: 4
• Pages: 502–518
• DOI: https://doi.org/10.1161/circresaha.119.316007
• Keywords: Physiology; Cardiology and Cardiovascular Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/4469831
• Publisher URL: https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.119.316007