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; Gerhard Christofori

doi:10.1038/s41467-019-13591-7

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 journal › Article › Research › peer-review

42 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 language	English
Article number	5755
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13591-7
Publication status	Published - 1 Dec 2019
Externally published	Yes

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Tang, F., Gao, R., Jeevan-Raj, B., Wyss, C. B., Kalathur, R. K. R., Piscuoglio, S., Ng, C. K. Y., Hindupur, S. K., Nuciforo, S., Dazert, E., Bock, T., Song, S., Buechel, D., Morini, M. F., Hergovich, A., Matthias, P., Lim, D. S., Terracciano, L. M., Heim, M. H., ... Christofori, G. (2019). LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function. Nature Communications, 10(1), Article 5755. https://doi.org/10.1038/s41467-019-13591-7

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title = "LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function",

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.",

author = "Fengyuan Tang and Ruize Gao and Beena Jeevan-Raj and Wyss, {Christof B.} and Kalathur, {Ravi K.R.} and Salvatore Piscuoglio and Ng, {Charlotte K.Y.} and Hindupur, {Sravanth K.} and Sandro Nuciforo and Eva Dazert and Thomas Bock and Shuang Song and David Buechel and Morini, {Marco F.} and Alexander Hergovich and Patrick Matthias and Lim, {Dae Sik} and Terracciano, {Luigi M.} and Heim, {Markus H.} and Hall, {Michael N.} and Gerhard Christofori",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

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doi = "10.1038/s41467-019-13591-7",

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Tang, F, Gao, R, Jeevan-Raj, B, Wyss, CB, Kalathur, RKR, Piscuoglio, S, Ng, CKY, Hindupur, SK, Nuciforo, S, Dazert, E, Bock, T, Song, S, Buechel, D, Morini, MF, Hergovich, A, Matthias, P, Lim, DS, Terracciano, LM, Heim, MH, Hall, MN & Christofori, G 2019, 'LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function', Nature Communications, vol. 10, no. 1, 5755. https://doi.org/10.1038/s41467-019-13591-7

TY - JOUR

T1 - LATS1 but not LATS2 represses autophagy by a kinase-independent scaffold function

AU - Tang, Fengyuan

AU - Gao, Ruize

AU - Jeevan-Raj, Beena

AU - Wyss, Christof B.

AU - Kalathur, Ravi K.R.

AU - Piscuoglio, Salvatore

AU - Ng, Charlotte K.Y.

AU - Hindupur, Sravanth K.

AU - Nuciforo, Sandro

AU - Dazert, Eva

AU - Bock, Thomas

AU - Song, Shuang

AU - Buechel, David

AU - Morini, Marco F.

AU - Hergovich, Alexander

AU - Matthias, Patrick

AU - Lim, Dae Sik

AU - Terracciano, Luigi M.

AU - Heim, Markus H.

AU - Hall, Michael N.

AU - Christofori, Gerhard

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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DO - 10.1038/s41467-019-13591-7

M3 - Article

C2 - 31848340

AN - SCOPUS:85076617930

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5755

ER -

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

Abstract

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