Park Hwan-Woo, Park Haeli, Ro Seung-Hyun, Jang Insook, Semple Ian A, Kim David N, Kim Myungjin, Nam Myeongjin, Zhang Deqiang, Yin Lei, Lee Jun Hee
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
1] Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Biological Science, Gachon University of Medicine and Science, Yeonsugu, Incheon 406-799, Republic of Korea.
Nat Commun. 2014 Jun 20;5:4233. doi: 10.1038/ncomms5233.
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.
在内质网（ER）长期应激时，细胞会减弱蛋白质翻译以防止未折叠蛋白的积累。在此我们表明，Sestrin2对这一过程至关重要。Sestrin2的表达由ER应激激活的转录因子CCAAT增强子结合蛋白β（c/EBPβ）诱导。一旦被诱导，Sestrin2通过抑制雷帕霉素复合物1（mTORC1）的哺乳动物靶点来停止蛋白质合成。由于Sestrin2缺陷细胞在ER应激期间继续翻译大量蛋白质，它们极易受到ER应激相关的细胞死亡影响。因此，饮食或基因诱导的肥胖，除了在野生型（WT）小鼠肝脏中单纯脂肪积累外不会导致任何病理表现，却能促使Sestrin2缺陷小鼠发展出严重的ER应激相关肝脏病变，如广泛的肝损伤、脂肪性肝炎和纤维化。这些病变可通过肝脏特异性Sestrin2重建、mTORC1抑制或给予化学伴侣来抑制。Sestrin2介导的未折叠蛋白反应（UPR）可能是针对ER应激相关疾病的一种普遍保护机制。
