A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response

Dan Shao, Peiyong Zhai, Dominic P. Del Re, Sebastiano Sciarretta, Norikazu Yabuta, Hiroshi Nojima, Dae-Sik Lim, Duojia Pan and Junichi Sadoshima ()
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Dan Shao: Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences
Peiyong Zhai: Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences
Dominic P. Del Re: Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences
Sebastiano Sciarretta: Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences
Norikazu Yabuta: Research Institute for Microbial Diseases, Osaka University
Hiroshi Nojima: Research Institute for Microbial Diseases, Osaka University
Dae-Sik Lim: National Creative Research Initiatives Center, Biomedical Research Center, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology
Duojia Pan: Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
Junichi Sadoshima: Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract The Hippo pathway is an evolutionarily conserved regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Here we report that Yes-associated protein (YAP), the terminal effector of the Hippo pathway, interacts with FoxO1 in the nucleus of cardiomyocytes, thereby promoting survival. YAP and FoxO1 form a functional complex on the promoters of the catalase and manganese superoxide dismutase (MnSOD) antioxidant genes and stimulate their transcription. Inactivation of YAP, induced by Hippo activation, suppresses FoxO1 activity and decreases antioxidant gene expression, suggesting that Hippo signalling modulates the FoxO1-mediated antioxidant response. In the setting of ischaemia/reperfusion (I/R) in the heart, activation of Hippo antagonizes YAP-FoxO1, leading to enhanced oxidative stress-induced cell death through downregulation of catalase and MnSOD. Conversely, restoration of YAP activity protects against I/R injury. These results suggest that YAP is a nuclear co-factor of FoxO1 and that the Hippo pathway negatively affects cardiomyocyte survival by inhibiting the function of YAP-FoxO1.

Date: 2014
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DOI: 10.1038/ncomms4315

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