Hepatoprotective role of Sestrin2 against chronic ER stress

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

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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 CCAAT-enhancer-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 stress-associated 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.

Date: 2014
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DOI: 10.1038/ncomms5233

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