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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & , 2019. "LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13591-7
    DOI: 10.1038/s41467-019-13591-7
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