p73 regulates autophagy and hepatocellular lipid metabolism through a transcriptional activation of the ATG5 gene

• Published in: Cell death and differentiation Vol. 20; no. 10; pp. 1415 - 1424
• Main Authors: He, Z, Liu, H, Agostini, M, Yousefi, S, Perren, A, Tschan, M P, Mak, T W, Melino, G, Simon, H U
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2013; Nature Publishing Group
• Subjects: 631/337/572; 631/443/319; 631/45/287; 631/80/82/39; Animals; Apoptosis; Apoptosis - physiology; Autophagy; Autophagy - physiology; Autophagy-Related Protein 5; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell cycle; Cell Cycle Analysis; Cell death; Cell Line, Tumor; DNA damage; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; HCT116 Cells; Homeostasis; Humans; Life Sciences; Lipid Metabolism - genetics; Lipids; Liver; Liver - cytology; Liver - metabolism; Liver - physiology; Medical research; Metabolism; Mice; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Original Paper; Proteins; Senescence; Stem Cells; Transcriptional Activation; Tumor Protein p73; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Tumors; Switzerland; Sudan; starvation; autophagy; transcription; liver; lipophagy; metabolism; lipid droplets; p73; ATG5
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.104

p73, a member of the p53 tumor suppressor family, is involved in neurogenesis, sensory pathways, immunity, inflammation, and tumorigenesis. How p73 is able to participate in such a broad spectrum of different biological processes is still largely unknown. Here, we report a novel role of p73 in regulating lipid metabolism by direct transactivation of the promoter of
autophagy-related protein 5 (ATG5)
, a gene whose product is required for autophagosome formation. Following nutrient deprivation, the livers of p73-deficient mice demonstrate a massive accumulation of lipid droplets, together with a low level of autophagy, suggesting that triglyceride hydrolysis into fatty acids is blocked owing to deficient autophagy (macrolipophagy). Compared with wild-type mice, mice functionally deficient in all the p73 isoforms exhibit decreased ATG5 expression and lower levels of autophagy in multiple organs. We further show that the TAp73
α
is the critical p73 isoform responsible for inducing ATG5 expression in a p53-independent manner and demonstrate that
ATG5
gene transfer can correct autophagy and macrolipophagy defects in p73-deficient hepatocytes. These data strongly suggest that the p73–ATG5 axis represents a novel, key pathway for regulating lipid metabolism through autophagy. The identification of p73 as a major regulator of autophagy suggests that it may have an important role in preventing or delaying disease and aging by maintaining a homeostatic control.