Hepatoprotective role of Sestrin2 against chronic ER stress

Authors

Hwan-Woo Park, University of Michigan-Ann Arbor
Haeli Park, University of Michigan-Ann Arbor
Seung-Hyun Ro, University of Michigan-Ann ArborFollow
Insook Jang, University of Michigan-Ann Arbor
Ian A. Semple, University of Michigan-Ann Arbor
David N. Kim, University of Michigan-Ann Arbor
Myungjin Kim, University of Michigan-Ann Arbor
Myeongjin Nam, University of Michigan-Ann Arbor
Deqiang Zhang, University of Michigan-Ann Arbor
Lei Yin, University of Michigan-Ann Arbor
Jun Hee Lee, University of Michigan-Ann ArborFollow

Document Type

Article

Date of this Version

2014

Citation

NATURE COMMUNICATIONS | 5:4233

Comments

© 2014 Macmillan Publishers Limited.

DOI: 10.1038/ncomms5233

Abstract

Upon prolonged endoplasmic reticulum (ER) stress, cells attenuate protein translation to prevent accumulation of unfolded proteins. Here we show that Sestrin2 is critical for this process. Sestrin2 expression is induced by an ER stress-activated transcription factor CCAATenhancer- binding protein beta (c/EBPβ). Once induced, Sestrin2 halts protein synthesis by inhibiting mammalian target of rapamycin complex 1 (mTORC1). As Sestrin2-deficient cells continue to translate a large amount of proteins during ER stress, they are highly susceptible to ER stress-associated cell death. Accordingly, dietary or genetically induced obesity, which does not lead to any pathological indication other than simple fat accumulation in the liver of wild-type (WT) mice, can provoke Sestrin2-deficient mice to develop severe ER stressassociated liver pathologies such as extensive liver damage, steatohepatitis and fibrosis. These pathologies are suppressed by liver-specific Sestrin2 reconstitution, mTORC1 inhibition or chemical chaperone administration. The Sestrin2-mediated unfolded protein response (UPR) may be a general protective mechanism against ER stress-associated diseases.