Parkin ubiquitinates mTOR to regulate mTORC1 activity under mitochondrial stress

Dohyun Park; Mi Nam Lee; Heeyoon Jeong; Ara Koh; Yong Ryoul Yang; Pann-Ghill Suh; Sung Ho Ryu

doi:10.1016/j.cellsig.2014.06.010

Parkin ubiquitinates mTOR to regulate mTORC1 activity under mitochondrial stress

Cell Signal. 2014 Oct;26(10):2122-30. doi: 10.1016/j.cellsig.2014.06.010. Epub 2014 Jul 5.

Authors

Dohyun Park¹, Mi Nam Lee¹, Heeyoon Jeong¹, Ara Koh¹, Yong Ryoul Yang², Pann-Ghill Suh², Sung Ho Ryu³

Affiliations

¹ Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
² School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 689-798, Republic of Korea.
³ Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea. Electronic address: [email protected].

PMID: 25007995
DOI: 10.1016/j.cellsig.2014.06.010

Abstract

mTORC1, a kinase complex that is considered a master regulator of cellular growth and proliferation, is regulated by many extra- and intracellular signals. Among these signals, mitochondrial status is known to have an impact on the effects of mTORC1 on cell growth and survival. However, how mitochondrial status affects mTORC1 activity, notably the molecular link, is not fully elucidated. Here, we found that Parkin can interact with and ubiquitinate mTOR. We also identified K2066 and K2306 as Parkin-dependent and mitochondrial stress-induced mTOR ubiquitination residues. This ubiquitination by Parkin is required for maintenance of mTORC1 activity under mitochondrial stress. With regard to the physiological meaning of mTORC1 activity under mitochondrial stress, we suggest that mTORC1 plays a pro-survival role.

Keywords: Mitochondrial stress; Parkin; Ubiquitination; mTOR; mTORC1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Apoptosis / drug effects
Carbonyl Cyanide m-Chlorophenyl Hydrazone / analogs & derivatives
Carbonyl Cyanide m-Chlorophenyl Hydrazone / toxicity
HEK293 Cells
Humans
Mechanistic Target of Rapamycin Complex 1
Mitochondria / drug effects
Mitochondria / metabolism*
Multiprotein Complexes / antagonists & inhibitors
Multiprotein Complexes / metabolism*
Protein Binding
RNA Interference
RNA, Small Interfering / metabolism
Regulatory-Associated Protein of mTOR
Sirolimus / toxicity
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism*
Ubiquitin-Protein Ligases / antagonists & inhibitors
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination

Substances

Adaptor Proteins, Signal Transducing
Multiprotein Complexes
RNA, Small Interfering
RPTOR protein, human
Regulatory-Associated Protein of mTOR
Carbonyl Cyanide m-Chlorophenyl Hydrazone
Ubiquitin-Protein Ligases
parkin protein
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases
Sirolimus