SNX13 reduction mediates heart failure through degradative sorting of apoptosis repressor with caspase recruitment domain

Li, Jun; Liu, Changming; Zhang, Dasheng; Shi, Dan; Qi, Man; Feng, Jing; Yuan, Tianyou; Xu, Xinran; Liang, Dandan; Xu, Liang; Zhang, Hong; Liu, Yi; Chen, Jinjin; Ye, Jiangchuan; Jiang, Weifang; Cui, Yingyu; Zhang, Yangyang; Peng, Luying; Zhou, Zhao-Nian; Chen, Yihan

doi:10.1038/ncomms6177

Cited by 40 publications

(35 citation statements)

References 20 publications

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“…In patients with end-stage HF, myocardial levels of IAP are decreased, which may increase the susceptibility of the heart to the pathological effects of excessive apoptosis [120]. Chen and colleagues have also suggested that ARC (apoptosis regulator with caspase recruitment domain), an apoptotic repressor prevalent in cardiac muscle, is degraded by deficiency of SNX13 (sorting nexin-13) with consequent increases in cardiac apoptosis, increases in cardiomyocyte death and worsened cardiac function [121]. Similarly, inhibition of XIAP by XAF1 (XIAP-interacting protein-1) promotes caspase-induced apoptosis in cardiac myocytes.…”

Section: Cardiomyocyte Death In Hfmentioning

confidence: 99%

Chronic heart failure: Ca 2+ , catabolism, and catastrophic cell death

Cho

Altamirano

Hill

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Robust successes have been achieved in recent years in conquering the acutely lethal manifestations of heart disease. Many patients who previously would have died now survive to enjoy happy and productive lives. Nevertheless, the devastating impact of heart disease continues unabated, as the spectrum of disease has evolved with new manifestations. In light of this ever-evolving challenge, insights that culminate in novel therapeutic targets are urgently needed. Here, we review fundamental mechanisms of heart failure, both with reduced (HFrEF) and preserved (HFpEF) ejection fraction. We discuss pathways that regulate cardiomyocyte remodeling and turnover, focusing on Ca2+ signaling, autophagy, and apoptosis. In particular, we highlight recent insights pointing to novel connections among these events. We also explore mechanisms whereby potential therapeutic approaches targeting these processes may improve morbidity and mortality in the devastating syndrome of heart failure.

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Section: Cardiomyocyte Death In Hfmentioning

confidence: 99%

Chronic heart failure: Ca 2+ , catabolism, and catastrophic cell death

Cho

Altamirano

Hill

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…ARC sorting may be disrupted under reduced SNX13 expression conditions, thereby causing ARC trafficking defects and premature degradation with subsequent caspase-8 over-activation and apoptotic cardiomyocyte death. Domain deletion approaches in this study suggest that the N-terminal PXA, but not PX, RGS and the PXC domains of SNX13 mediates ARC endosomal sorting (50).…”

Section: Are the Rgs-snx Proteins A New Family Of Endosomal Membrane mentioning

confidence: 72%

“…This also suggests that other SNX-RGS proteins are unable to compensate for SNX13 loss. Li et al (2014), reported that SNX13 deficiency correlates with severe heart failure and thus might have a potential role in the regulation of cardiac function (50). SNX19 is expressed in a broad range of tissues including stomach, intestine and stronger levels in testis.…”

Section: What We Know So Far About the Functions Of Snx-rgs Proteinsmentioning

confidence: 99%

“…Until recently the only report on the functions of the poorly characterised PXA and PXC domains was that the SNX25 PXA domain was able to localise to EEA1-positive endosomes independently of the other domains and was important in the role of SNX25 in TGF-β receptor degradation (38,51). In 2014, a new study suggested that SNX13 expression levels might be correlated with heart failure (50). This study found that reduction in SNX13 expression facilitated lysosomal degradative sorting of apoptosis repressor with caspase recruitment domain (ARC).…”

Section: Are the Rgs-snx Proteins A New Family Of Endosomal Membrane mentioning

confidence: 99%

“…This study found that reduction in SNX13 expression facilitated lysosomal degradative sorting of apoptosis repressor with caspase recruitment domain (ARC). This process leads to apoptotic pathway activation, and results in the loss of cardiac cells and thus a decrease in cardiac function (50). Expression of ARC in the heart has cardioprotective functions against development of heart failure by inhibiting intrinsic and extrinsic apoptotic death pathways through inhibiting caspase-8 activity (58).…”

Section: Are the Rgs-snx Proteins A New Family Of Endosomal Membrane mentioning

confidence: 99%

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Structural studies of sorting nexin proteins from two distinct subfamilies

Paul¹

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Sorting nexin (SNX) proteins are a large family of proteins with critical roles in endocytosis, membrane trafficking and intracellular signalling. Each SNX protein contains a Phox homology (PX) domain that typically recognizes phosphoinositide lipids to enable their anchoring to defined organelles. SNXs also contain additional domains other than the PX domain thus allowing them to participate in a wide range of functions such as proteinprotein interactions, membrane remodeling, lipid metabolism and other functions that are yet to be explored. My research focuses on the structural and functional characterization of two different sub-families of SNX proteins; those that have both PX and BAR (bin/amphiphysin/rvs) domains (SNX5, SNX6 and SNX32), and the poorly characterized SNX-RGS sub-family that contain a regulator of G-protein signaling (RGS) domain (SNX13, SNX14, SNX19 and SNX25). These protein families are required for membrane trafficking and lipid droplet formation, and are implicated in diseases including pathogen invasion and cerebellar ataxia respectively. I first describe the structural mechanism for how a Chlamydial effector protein called IncE hijacks and recruits SNX5 related proteins to the bacterial inclusion membrane during Chlamydial infection (Chapter 2). Using X-ray crystallography, I demonstrate that the Cterminal region of IncE forms a β-hairpin structure and binds to a unique α-helical insertion on the PX domain of SNX5, which is a separate site from the canonical PX lipid-binding site. Using isothermal titration calorimetry, I also investigate the binding mechanisms of the SNX5 homologs, SNX6 and SNX32 to IncE, and demonstrate that these three proteins share a common binding mechanism. These results suggest that the IncE protein mimics other SNX5-related proteins, where SNX5 PX might be functioning as a protein-binding scaffold that could potentially orchestrate the trafficking of certain transmembrane receptors.The research presented in Chapter 3 extends the work described in Chapter 2 confirming the IncE binding site in the SNX32 PX domain using X-ray crystallography. The crystal structure of SNX32 PX-IncE complex not only confirmed the biophysical data from chapter 2, but also revealed the binding mechanism to be identical to the SNX5PX-IncE binding. In addition, this is the first reported structure of the SNX32 protein in either an apo or ligand bound state. This result further strengthens the idea that SNX-BAR proteins can act as receptor recyclers in the cell.In Chapter 4 using biophysical and structural studies, I next investigated the potential functional role of the SNX-BAR proteins in transmembrane cargo trafficking. My biophysical experiments directly confirmed the recent indirect proteomic studies that Conference abstractsStructural basis for the hijacking of endosomal sorting nexin proteins by Chlamydia trachomatis.

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Inhibition of microRNA‐327 ameliorates ischemia/reperfusion injury‐induced cardiomyocytes apoptosis through targeting apoptosis repressor with caspase recruitment domain

Yang

Zhang

et al. 2019

Journal Cellular Physiology

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Apoptosis is the major cause of cardiomyocyte death in myocardial ischemia/reperfusion injury (MI/RI). Increasing evidence suggests that microRNAs (miRNAs) can contribute to the regulation of cardiomyocytes apoptosis by posttranscriptional modulation of gene expression networks. However, the effects of miR-327 in regulating MI/RI-induced cardiomyocytes apoptosis have not been extensively investigated. This study was performed to test whether miR-327 participate in cardiomyocytes apoptosis both in vitro and in vivo, and reveal the potential molecular mechanism of miR-327 regulated MI/RI through targeting apoptosis repressor with caspase recruitment domain (ARC).Sprague-Dawley (SD) rats were subjected to MI/RI by left anterior descending coronary artery occlusion for 30 min and reperfusion for 3 hr. H9c2 cells were exposed to hypoxia for 4 hr and reoxygenation for 12 hr to mimic I/R injury. miRNA-327 recombinant adenovirus vectors were transfected into H9c2 cells for 48 hr and rats for 72 hr before H/R and MI/RI treatment, respectively. The apoptosis rate, downstream molecules of apoptotic pathway, and the target reaction between miRNA-327 and ARC were evaluated.Our results showed that miR-327 was upregulated and ARC was downregulated in the myocardial tissues of MI/RI rats and in H9c2 cells with H/R treatment. Inhibition of miR-327 decreased the expression levels of proapoptotic proteins Fas, FasL, caspase-8, Bax, cleaved caspase-9, cleaved caspase-3, and the release of cytochrome-C, as well as increasing the expression levels of antiapoptotic protein Bcl-2 via negative regulation of ARC both in vivo or vitro. In contrast, overexpression miR-327 showed the reverse effect.Moreover, the results of luciferase reporter assay indicated miR-327 targets ARC directly at the posttranscriptional level. Taken together, inhibition of miR-327 could attenuate cardiomyocyte apoptosis and alleviate I/R-induced myocardial injury via targeting ARC, which offers a new therapeutic strategy for MI/RI.

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SNX13 reduction mediates heart failure through degradative sorting of apoptosis repressor with caspase recruitment domain

Cited by 40 publications

References 20 publications

Chronic heart failure: Ca 2+ , catabolism, and catastrophic cell death

Chronic heart failure: Ca 2+ , catabolism, and catastrophic cell death

Structural studies of sorting nexin proteins from two distinct subfamilies

Inhibition of microRNA‐327 ameliorates ischemia/reperfusion injury‐induced cardiomyocytes apoptosis through targeting apoptosis repressor with caspase recruitment domain

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