Page 24 - ebook

[A. Biochemistry/Molecular Biology] A-12

Tfeb-mediated transcriptional regulation of autophagy

induces autosis during ischemia/reperfusion in the heart

Jihoon Nah¹,² , Eun-Ah Sung² , Peiyong Zhai², Junichi Sadoshima²*
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¹School of Biological Sciences, Seoul National University, Seoul 08826, Korea, ²Cell Biology and Molecular

Medicine, Rutgers University, Newark 07103, USA

Autosis is a unique form of cell death with characteristic morphological and biochemical features caused by

dysregulated autophagy. We have shown previously that excessive accumulation of autophagosomes promotes
autosis in cardiomyocytes. Although the inhibition of autophagic flux via upregulation of Rubicon induces

accumulation of autophagosomes during I/R, it appears that additional mechanisms exacerbating autophagosome
accumulation are required for the induction of autosis. Here we show that Tfeb contributes to the induction of

autosis during the late phase of I/R in the heart. During myocardial reperfusion, Tfeb is activated and translocated
into the nucleus, which in turn upregulates genes involved in autophagy and lysosomal function. Overexpression of

Tfeb enhanced cardiomyocyte death induced by a high dose of TAT-Beclin 1, an effect that was inhibited by
downregulation of Atg7. Conversely, knock-down of Tfeb attenuated high dose TAT-Beclin1-induced death in

cardiomyocytes. Although down-regulation of Tfeb in the heart significantly decreased the number of autophagic
vacuoles and inhibited autosis during I/R, activation of Tfeb activity by 3,4-dimethoxychalcone, an activator of Tfeb,

aggravated myocardial injury during I/R. These findings suggest that Tfeb promotes cardiomyocyte autosis during
the late phase of reperfusion in the heart.