Jnk2 Promotes Stress-induced Mitophagy and Suppresses Inflammasome Activation by Targeting Smarf for Degradation
Jnk2 Promotes Stress-induced Mitophagy and Suppresses Inflammasome Activation by Targeting Smarf for Degradation
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通讯作者：
Qiao Zhang;Hong Kuang;Cong Chen;Jie Yan;Hanh Chi Do-Umehara;Xin-Yuan Liu;L. Dada;K. Ridge;N. Chandel;Jing Liu
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作者：
Qiao Zhang;Hong Kuang;Cong Chen;Jie Yan;Hanh Chi Do-Umehara;Xin-Yuan Liu;L. Dada;K. Ridge;N. Chandel;Jing Liu
线粒体自噬对于细胞稳态至关重要，但其调节机制很大程度上未知。在这里，我们报告激酶 Jnk2 是应激诱导的线粒体自噬所必需的。 Jnk2 促进小线粒体形式 ARF (smARF) 的泛素化和蛋白酶体降解。 Jnk2 的缺失导致 smARF 的积累，进而诱导过度的自噬活性，导致稳定状态下线粒体自噬接头 p62 的溶酶体降解。 p62 的消耗阻止了 Jnk2 缺陷细胞在应激时进行线粒体自噬。 Jnk2缺陷的小鼠表现出有缺陷的线粒体自噬，导致缺氧应激下的组织损伤，以及炎症小体的过度激活和败血症死亡率的增加。我们的发现定义了维持免疫稳态的独特机制，可保护宿主免受组织损伤和死亡。
Mitophagy is essential for cellular homeostasis but the regulatory mechanism is largely unknown. Here we report that the kinase Jnk2 is required for stress-induced mitophagy. Jnk2 promoted ubiquitination and proteasomal degradation of small mitochondrial form of ARF (smARF). Loss of Jnk2 led to accumulation of smARF, which in turn induced excessive autophagic activity, resulting in lysosomal degradation of the mitophagy adaptor p62 in the steady state. The depletion of p62 prevented Jnk2-deficient cells from mounting mitophagy upon stress. Jnk2-deficient mice displayed defective mitophagy, resulting in tissue damage under hypoxic stress, as well as hyperactivation of inflammasome and increased mortality in sepsis. Our finding defines a unique mechanism of maintaining immune homeostasis that protects the host from tissue damage and mortality.