LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

Fengyuan Tang (), Ruize Gao, Beena Jeevan-Raj, Christof B. Wyss, Ravi K. R. Kalathur, Salvatore Piscuoglio, Charlotte K. Y. Ng, Sravanth K. Hindupur, Sandro Nuciforo, Eva Dazert, Thomas Bock, Shuang Song, David Buechel, Marco F. Morini, Alexander Hergovich, Patrick Matthias, Dae-Sik Lim, Luigi M. Terracciano, Markus H. Heim, Michael N. Hall and Gerhard Christofori ()
Additional contact information
Fengyuan Tang: University of Basel
Ruize Gao: University of Basel
Beena Jeevan-Raj: University of Basel
Christof B. Wyss: University of Basel
Ravi K. R. Kalathur: University of Basel
Salvatore Piscuoglio: University Hospital Basel
Charlotte K. Y. Ng: University Hospital Basel
Sravanth K. Hindupur: Biozentrum, University of Basel
Sandro Nuciforo: University of Basel
Eva Dazert: Biozentrum, University of Basel
Thomas Bock: Biozentrum, University of Basel
Shuang Song: Friedrich Miescher Institute for Biomedical Research
David Buechel: University of Basel
Marco F. Morini: University of Basel
Alexander Hergovich: University College London
Patrick Matthias: Friedrich Miescher Institute for Biomedical Research
Dae-Sik Lim: Korea Advanced Institute of Science and Technology
Luigi M. Terracciano: University Hospital Basel
Markus H. Heim: University of Basel
Michael N. Hall: Biozentrum, University of Basel
Gerhard Christofori: University of Basel

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Autophagy perturbation represents an emerging therapeutic strategy in cancer. Although LATS1 and LATS2 kinases, core components of the mammalian Hippo pathway, have been shown to exert tumor suppressive activities, here we report a pro-survival role of LATS1 but not LATS2 in hepatocellular carcinoma (HCC) cells. Specifically, LATS1 restricts lethal autophagy in HCC cells induced by sorafenib, the standard of care for advanced HCC patients. Notably, autophagy regulation by LATS1 is independent of its kinase activity. Instead, LATS1 stabilizes the autophagy core-machinery component Beclin-1 by promoting K27-linked ubiquitination at lysine residues K32 and K263 on Beclin-1. Consequently, ubiquitination of Beclin-1 negatively regulates autophagy by promoting inactive dimer formation of Beclin-1. Our study highlights a functional diversity between LATS1 and LATS2, and uncovers a scaffolding role of LATS1 in mediating a cross-talk between the Hippo signaling pathway and autophagy.

Date: 2019
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DOI: 10.1038/s41467-019-13591-7

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