Lu Jiahong, He Liqiang, Behrends Christian, Araki Masatake, Araki Kimi, Jun Wang Qing, Catanzaro Joseph M, Friedman Scott L, Zong Wei-Xing, Fiel M Isabel, Li Min, Yue Zhenyu
1] Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA [2] School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China [3].
1] Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA [2].
Nat Commun. 2014 May 22;5:3920. doi: 10.1038/ncomms4920.
The Beclin 1-Vps34 complex, the core component of the class III phosphatidylinositol-3 kinase (PI3K-III), binds Atg14L or UVRAG to control different steps of autophagy. However, the mechanism underlying the control of PI3K-III activity remains elusive. Here we report the identification of NRBF2 as a component in the specific PI3K-III complex and a modulator of PI3K-III activity. Through its microtubule interaction and trafficking (MIT) domain, NRBF2 binds Atg14L directly and enhances Atg14L-linked Vps34 kinase activity and autophagy induction. NRBF2-deficient cells exhibit enhanced vulnerability to endoplasmic reticulum (ER) stress that is reversed by re-introducing exogenous NRBF2. NRBF2-deficient mice develop focal liver necrosis and ductular reaction, accompanied by impaired Atg14L-linked Vps34 activity and autophagy, although the mice show no increased mortality. Our data reveal a key role for NRBF2 in the assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction. Thus, NRBF2 modulates autophagy via regulation of PI3K-III and prevents ER stress-mediated cytotoxicity and liver injury.
Beclin 1-Vps34复合物是III类磷脂酰肌醇-3激酶（PI3K-III）的核心成分，它与Atg14L或UVRAG结合以控制自噬的不同步骤。然而，PI3K-III活性调控的潜在机制仍不清楚。在此，我们报告鉴定出NRBF2是特定PI3K-III复合物的一个成分以及PI3K-III活性的调节剂。通过其微管相互作用和运输（MIT）结构域，NRBF2直接结合Atg14L并增强Atg14L相关的Vps34激酶活性及自噬诱导。NRBF2缺陷型细胞对内质网（ER）应激表现出增强的易感性，重新引入外源性NRBF2可逆转这种情况。NRBF2缺陷型小鼠发生局灶性肝坏死和胆管反应，伴有Atg14L相关的Vps34活性及自噬受损，尽管这些小鼠的死亡率没有增加。我们的数据揭示了NRBF2在自噬诱导的特定Atg14L-Beclin 1-Vps34-Vps15复合物组装中的关键作用。因此，NRBF2通过调节PI3K-III来调节自噬，并预防ER应激介导的细胞毒性和肝损伤。
