Polycystin-2-dependent control of cardiomyocyte autophagy

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Item Type:	Article
Title:	Polycystin-2-dependent control of cardiomyocyte autophagy
Creators Name:	Criollo, A., Altamirano, F., Pedrozo, Z., Schiattarella, G.G., Li, D.L., Rivera-Mejías, P., Sotomayor-Flores, C., Parra, V., Villalobos, E., Battiprolu, P.K., Jiang, N., May, H.I., Morselli, E., Somlo, S., de Smedt, H., Gillette, T.G., Lavandero, S. and Hill, J.A.
Abstract:	AIMS: Considerable evidence points to critical roles of intracellular Ca(2+) homeostasis in the modulation and control of autophagic activity. Yet, underlying molecular mechanisms remain unknown. Mutations in the gene (pkd2) encoding polycystin-2 (PC2) are associated with autosomal dominant polycystic kidney disease (ADPKD), the most common inherited nephropathy. PC2 has been associated with impaired Ca(2+) handling in cardiomyocytes and indirect evidence suggests that this protein may be involved in autophagic control. Here, we investigated the role for PC2 as an essential regulator of Ca(2+) homeostasis and autophagy. METHODS AND RESULTS: Activation of autophagic flux triggered by mTOR inhibition either pharmacologically (rapamycin) or by means of nutrient depletion was suppressed in cells depleted of PC2. Moreover, cardiomyocyte-specific PC2 knockout mice (αMhc-cre;Pkd2(F/F) mice) manifested impaired autophagic flux in the setting of nutrient deprivation. Stress-induced autophagy was blunted by intracellular Ca(2+) chelation using BAPTA-AM, whereas removal of extracellular Ca(2+) had no effect, pointing to a role of intracellular Ca(2+) homeostasis in stress-induced cardiomyocyte autophagy. To determine the link between stress-induced autophagy and PC2-induced Ca(2+) mobilization, we over-expressed either wild-type PC2 (WT) or a Ca(2+)-channel deficient PC2 mutant (PC2-D509V). PC2 over-expression increased autophagic flux, whereas PC2-D509V expression did not. Importantly, autophagy induction triggered by PC2 over-expression was attenuated by BAPTA-AM, supporting a model of PC2-dependent control of autophagy through intracellular Ca(2+). Furthermore, PC2 ablation was associated with impaired Ca(2+) handling in cardiomyocytes marked by partial depletion of sarcoplasmic reticulum Ca(2+) stores. Finally, we provide evidence that Ca(2+)-mediated autophagy elicited by PC2 is a mechanism conserved across multiple cell types. CONCLUSION: Together, this study unveils PC2 as a novel regulator of autophagy acting through control of intracellular Ca(2+) homeostasis.
Keywords:	Polycystin-2, Autophagy, Stress, Heart, Calcium, Animals, Mice
Source:	Journal of Molecular and Cellular Cardiology
ISSN:	0022-2828
Publisher:	Elsevier
Volume:	118
Page Range:	110-121
Date:	May 2018
Official Publication:	https://doi.org/10.1016/j.yjmcc.2018.03.002
PubMed:	View item in PubMed

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