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. HallGerhard Christofori

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

34 Citations (Scopus)

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.

Original languageEnglish
Article number5755
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019
Externally publishedYes

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