Identification of ROCK1 kinase as a critical regulator of Beclin1-mediated autophagy during metabolic stress

Aditi U. Gurkar, Kiki Chu, Lakshmi Raj, Richard Bouley, Seung-Hwan Lee, Young-Bum Kim, Sandra E. Dunn, Anna Mandinova and Sam W. Lee ()
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Aditi U. Gurkar: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149 13th Street, Charlestown, Massachusetts 02129, USA
Kiki Chu: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149 13th Street, Charlestown, Massachusetts 02129, USA
Lakshmi Raj: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149 13th Street, Charlestown, Massachusetts 02129, USA
Richard Bouley: Simches Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA
Seung-Hwan Lee: Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School
Young-Bum Kim: Diabetes, and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School
Sandra E. Dunn: University of British Columbia
Anna Mandinova: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149 13th Street, Charlestown, Massachusetts 02129, USA
Sam W. Lee: Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149 13th Street, Charlestown, Massachusetts 02129, USA

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: Abstract The Ser/Thr Rho kinase 1 (ROCK1) is known to have major roles in a wide range of cellular activities, including those involved in tumour metastasis and apoptosis. Here we identify an indispensable function of ROCK1 in metabolic stress-induced autophagy. Applying a proteomics approach, we characterize Beclin1, a proximal component of the phosphoinositide 3-kinase class III lipid–kinase complex that induces autophagy, as an interacting partner of ROCK1. Upon nutrient deprivation, activated ROCK1 promotes autophagy by binding and phosphorylating Beclin1 at Thr119. This results in the specific dissociation of the Beclin1–Bcl-2 complex without affecting the Beclin1–UVRAG interaction. Conversely, inhibition of ROCK1 activity increases Beclin1–Bcl-2 association, thus reducing nutritional stress-mediated autophagy. Genetic knockout of ROCK1 function in mice also leads to impaired autophagy as evidenced by reduced autophagosome formation. These results show that ROCK1 acts as a prominent upstream regulator of Beclin1-mediated autophagy and maintains a homeostatic balance between apoptosis and autophagy.

Date: 2013
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DOI: 10.1038/ncomms3189

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