Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nat Commun. 2013;4:2189. doi: 10.1038/ncomms3189.
The Ser/Thr Rho kinase 1 (ROCK1) is known to have major roles in a wide range of cellular activities, including those involved in tumour metastasis and apoptosis. Here we identify an indispensable function of ROCK1 in metabolic stress-induced autophagy. Applying a proteomics approach, we characterize Beclin1, a proximal component of the phosphoinositide 3-kinase class III lipid-kinase complex that induces autophagy, as an interacting partner of ROCK1. Upon nutrient deprivation, activated ROCK1 promotes autophagy by binding and phosphorylating Beclin1 at Thr119. This results in the specific dissociation of the Beclin1-Bcl-2 complex without affecting the Beclin1-UVRAG interaction. Conversely, inhibition of ROCK1 activity increases Beclin1-Bcl-2 association, thus reducing nutritional stress-mediated autophagy. Genetic knockout of ROCK1 function in mice also leads to impaired autophagy as evidenced by reduced autophagosome formation. These results show that ROCK1 acts as a prominent upstream regulator of Beclin1-mediated autophagy and maintains a homeostatic balance between apoptosis and autophagy.
丝氨酸/苏氨酸 Rho 激酶 1（ROCK1）已知在广泛的细胞活动中具有重要作用，包括参与肿瘤转移和细胞凋亡。在这里，我们确定了 ROCK1 在代谢应激诱导的自噬中的不可或缺的功能。应用蛋白质组学方法，我们将 Beclin1 鉴定为磷酸肌醇 3-激酶 III 脂质激酶复合物的近端成分，该复合物诱导自噬，是 ROCK1 的相互作用伙伴。在营养剥夺时，激活的 ROCK1 通过与 Beclin1 的 Thr119 结合和磷酸化来促进自噬。这导致 Beclin1-Bcl-2 复合物的特异性解离，而不影响 Beclin1-UVRAG 相互作用。相反，抑制 ROCK1 活性会增加 Beclin1-Bcl-2 的结合，从而减少营养应激介导的自噬。在小鼠中敲除 ROCK1 功能也会导致自噬受损，这表现在自噬体形成减少。这些结果表明 ROCK1 作为 Beclin1 介导的自噬的主要上游调节剂发挥作用，并维持细胞凋亡和自噬之间的体内平衡。
