AMPK‐mediated degradation of Nav1.5 through autophagy

Liu, Xuehua; Chen, Zheng; Han, Zhonglin; Liu, Yu; Wu, Xiang; Peng, Yongjun; Di, Wencheng; Lan, Rongfang; Sun, Bo; Xu, Baojun; Xu, Wei

doi:10.1096/fj.201801583rr

Cited by 12 publications

(12 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The FAT10 protein is not unique in regards to the regulation of Nav1.5 ubiquitination, as several proteins have been demonstrated to participate in this process, such as UBC9 25 , UBR3, and UBR6 26 . Furthermore, under ischemia or hypoxia, the UBS and autophagic activities were increased 7,27 , which was potentially responsible for the decreased Nav1.5 protein expression 5,24 However, the degradation of Nav1.5 could partially but not totally be rescued by the increased FAT10 expression under the conduction of ischemia by antagonizing Nav1.5 ubiquitination, demonstrating a cardioprotective effect of FAT10. These results might explain the increased FAT10 expression and decreased Nav1.5 expression under ischemic/hypoxia conditions.…”

Section: Discussionmentioning

confidence: 96%

“…Interestingly, we found that FAT10 expression was increased, while that of Nav1.5 was decreased under hypoxic conditions, and several factors may underlie this result. First, the degradation of Nav1.5 is regulated by complex molecular mechanisms, such as ubiquitination 5 and autophagy 24 . In the present study, FAT10 overexpression stabilized the Nav1.5 protein by regulating its ubiquitination.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

FAT10 protects against ischemia-induced ventricular arrhythmia by decreasing Nedd4-2/Nav1.5 complex formation

et al. 2021

View full text Add to dashboard Cite

The human leukocyte antigen F-associated transcript 10 (FAT10) is a member of the small ubiquitin-like protein family that binds to its target proteins and subjects them to degradation by the ubiquitin–proteasome system (UPS). In the heart, FAT10 plays a cardioprotective role and affects predisposition to cardiac arrhythmias after myocardial ischemia (MI). However, whether and how FAT10 influences cardiac arrhythmias is unknown. We investigated the role of FAT10 in regulating the sodium channel Nav1.5, a major regulator of cardiac arrhythmias. Fat10 was conditionally deleted in cardiac myocytes using Myh6-Cre and Fat10F/F mice (cFat10−/−). Compared with their wild-type littermates, cFat10−/− mice showed prolonged RR, PR, and corrected QT (QTc) intervals, were more likely to develop ventricular arrhythmia, and had increased mortality after MI. Patch-clamp studies showed that the peak Na+ current was reduced, and the late Na+ current was significantly augmented, resulting in a decreased action potential amplitude and delayed depolarization. Immunoblot and immunofluorescence analyses showed that the expression of the membrane protein Nav1.5 was decreased. Coimmunoprecipitation experiments demonstrated that FAT10 stabilized Nav1.5 expression by antagonizing Nav1.5 ubiquitination and degradation. Specifically, FAT10 bound to the lysine residues in the C-terminal fragments of Nav1.5 and decreased the binding of Nav1.5 to the Nedd4-2 protein, a ubiquitin E3 ligase, preventing degradation of the Nav1.5 protein. Collectively, our findings showed that deletion of the Fat10 in cardiac myocytes led to increased cardiac arrhythmias and increased mortality after MI. Thus, FAT10 protects against ischemia-induced ventricular arrhythmia by binding to Nav1.5 and preventing its Neddylation and degradation by the UPS after MI.

show abstract

Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

FAT10 protects against ischemia-induced ventricular arrhythmia by decreasing Nedd4-2/Nav1.5 complex formation

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Previous studies showed that AMPK interacts with and phosphorylated CFTR to negatively regulate CFTR function (34,36,37). Additionally, AMPK interacts with and phosphorylates Na V 1.5 to regulate the interaction of Na V 1.5 with LC3 that is important for autophagic degradation (35). Considering that AMPK interacts with TRPM8 via the cytoplasmic C-terminus in a protein complex, additional studies are needed to determine whether and how AMPK phosphorylates TRPM8 at the C-terminus to modulate TRPM8 function.…”

Section: Discussionmentioning

confidence: 99%

“…AMPK interacts with ion channels, including sodium channel Na V 1.5 and the cystic fibrosis transmembrane conductance regulator (CFTR), forming a protein complex (34)(35)(36)(37). Thus, we aimed to determine whether TRPM8 directly interacts with AMPK to promote AMPK activation and phosphorylation.…”

Section: Trpm8-ampk Interaction Leads To Ampk Activation To Enhance Cmentioning

confidence: 99%

Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy

et al. 2020

View full text Add to dashboard Cite

The calcium-permeable cation channel TRPM8 (transient receptor potential melastatin 8) is a member of the TRP superfamily of cation channels that is upregulated in various types of cancer with high levels of autophagy, including prostate, pancreatic, breast, lung, and colon cancers. Autophagy is closely regulated by AMP-activated protein kinase (AMPK) and plays an important role in tumor growth by generating nutrients through degradation of intracellular structures. Additionally, AMPK activity is regulated by intracellular Ca2+ concentration. Considering that TRPM8 is a non-selective Ca2+-permeable cation channel and plays a key role in calcium homoeostasis, we hypothesized that TRPM8 may control AMPK activity thus modulating cellular autophagy to regulate the proliferation and migration of breast cancer cells. In this study, overexpression of TRPM8 enhanced the level of basal autophagy, whereas TRPM8 knockdown reduced the level of basal autophagy in several types of mammalian cancer cells. Moreover, the activity of the TRPM8 channel modulated the level of basal autophagy. The mechanism of regulation of autophagy by TRPM8 involves autophagy-associated signaling pathways for activation of AMPK and ULK1 and phagophore formation. Impaired AMPK abolished TRPM8-dependent regulation of autophagy. TRPM8 interacts with AMPK in a protein complex, and cytoplasmic C-terminus of TRPM8 mediates the TRPM8–AMPK interaction. Finally, basal autophagy mediates the regulatory effects of TRPM8 on the proliferation and migration of breast cancer cells. Thus, this study identifies TRPM8 as a novel regulator of basal autophagy in cancer cells acting by interacting with AMPK, which in turn activates AMPK to activate ULK1 in a coordinated cascade of TRPM8-mediated breast cancer progression.

show abstract

“…SCN5A alterations, either up-or downregulation, are known to cause arrhythmias, and SCN5A is downregulated in ischemic cardiomyopathy (27)(28)(29). Nevertheless, the mechanisms whereby ischemia causes a reduction in SCN5A have not been fully explored but include mRNA destabilization (9,27).…”

Section: Discussionmentioning

confidence: 99%

MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel

Kang¹,

Xie²,

Liu³

et al. 2020

JCI Insight

View full text Add to dashboard Cite

show abstract

AMPK‐mediated degradation of Nav1.5 through autophagy

Cited by 12 publications

References 47 publications

FAT10 protects against ischemia-induced ventricular arrhythmia by decreasing Nedd4-2/Nav1.5 complex formation

FAT10 protects against ischemia-induced ventricular arrhythmia by decreasing Nedd4-2/Nav1.5 complex formation

Transient Receptor Potential Melastatin 8 (TRPM8) Channel Regulates Proliferation and Migration of Breast Cancer Cells by Activating the AMPK-ULK1 Pathway to Enhance Basal Autophagy

MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel

Contact Info

Product

Resources

About