Regulation of autophagic flux by dynein-mediated autophagosomes trafficking in mouse coronary arterial myocytes
Ming Xu, Xiao-xue Li, Jing Xiong, Min Xia, Erich Gulbins, Yang Zhang, Pin-Lan Li
Index: Biochim. Biophys. Acta 1833(12) , 3228-36, (2013)
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Abstract
Autophagic flux is an important process during autophagy maturation in coronary arterial myocytes (CAMs). Here, we defined the role and molecular mechanism of the motor protein dynein in the regulation of autophagic flux in CAMs. In mouse CAMs, dynein protein is abundantly expressed. Pharmacological or genetic inhibition of dynein activity dramatically enhanced 7-ketocholesterol (7-Ket)-induced expression of the autophagic marker LC3B and increased the cellular levels of p62, a selective substrate for autophagy. Inhibition of dynein activity increased 7-Ket-induced formation of autophagosomes (APs), but reduced the number of autophagolysosomes (APLs) in CAMs. Furthermore, 7-Ket increased the fusion of APs with lysosomes and the velocity of APs movement in mouse CAMs, which was abolished when the dynein activity in these cells was inhibited. Interestingly, 7-Ket increased lysosomal Ca2+ release and stimulated dynein ATPase activity, both of which were abolished by NAADP antagonists, NED-19 and PPADS. Taken together, our data suggest that NAADP-mediated Ca2+ release plays a crucial role in regulating dynein activity, which mediates APs trafficking and fusion with lysosomes to form APLs thus regulating autophagic flux in CAMs under atherogenic stimulation.
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