Regulation of autophagosome formation by Rho kinase

Andrzej Mleczak, Sarah Millar, Sharon A Tooze, Michael F Olson, Edmond Y W Chan

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Macroautophagy, commonly referred to as autophagy, is a protein degradation pathway that functions at a constitutive level in cells, which may become further activated by stressors such as nutrient starvation or protein aggregation. Autophagy has multiple beneficial roles for maintaining normal cellular homeostasis and these roles are related to the implications of autophagy in disease mechanisms including neurodegeneration and cancer. We previously searched for novel autophagy regulators and identified Rho-kinase 1 (ROCK1) as a candidate. Here, we show that activated ROCK1 inhibits autophagy in human embryonic kidney 293 cells. Conversely, ROCK inhibitory compounds enhanced the autophagy response to amino acid starvation or rapamycin treatment. Inhibition of ROCK during the starvation period led to a more rapid response with the production of larger early autophagosomes that matured into enlarged late degradative autolysosomes. Despite the production of enlarged LC3-positive early autophagosomes, membrane precursors containing WD-repeat protein interacting with phosphoinositides 1 (WIPI1) and mammalian Atg9 were not affected by ROCK inhibition, suggesting that phagophore elongation had been unusually extended. However, the enlarged autophagosomes were enriched in ULK1 which was essential to allow progression of autophagy flux. Our results demonstrate a novel role for ROCK in the control of autophagosome size and degradative capacity.
Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalCellular Signalling
Volume25
Issue number1
Early online date10 Sep 2012
DOIs
Publication statusPublished - Jan 2013

Keywords

  • ROCK
  • Rho kinase
  • autophagy
  • autophagosome
  • lysosome

Cite this

Mleczak, A., Millar, S., Tooze, S. A., Olson, M. F., & Chan, E. Y. W. (2013). Regulation of autophagosome formation by Rho kinase. Cellular Signalling, 25(1), 1-11. https://doi.org/10.1016/j.cellsig.2012.09.010