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首页> 外文期刊>Molecular and Cellular Biology >Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik
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Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik

机译：靶向SQSTM1 / p62导致货物装载失败，并通过NBK / Bik将自噬转变为凋亡

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In selective autophagy, the adaptor protein SQSTM1/p62 plays a critical role in recognizing/loading cargo (e.g., malfolded proteins) into autophagosomes for lysosomal degradation. Here we report that whereas SQSTM1/p62 levels fluctuated in a time-dependent manner during autophagy, inhibition or knockdown of Cdk9/cyclin T1 transcriptionally downregulated SQSTM1/p62 but did not affect autophagic flux. These interventions, or short hairpin RNA (shRNA) directly targeting SQSTM1/p62, resulted in cargo loading failure and inefficient autophagy, phenomena recently described for Huntington's disease neurons. These events led to the accumulation of the BH3-only protein NBK/Bik on endoplasmic reticulum (ER) membranes, most likely by blocking loading and autophagic degradation of NBK/Bik, culminating in apoptosis. Whereas NBK/Bik upregulation was further enhanced by disruption of distal autophagic events (e.g., autophagosome maturation) by chloroquine (CQ) or Lamp2 shRNA, it was substantially diminished by inhibition of autophagy initiation (e.g., genetically by shRNA targeting Ulk1, beclin-1, or Atg5 or pharmacologically by 3-methyladenine [3-MA] or spautin-1), arguing that NBK/Bik accumulation stems from inefficient autophagy. Finally, NBK/Bik knockdown markedly attenuated apoptosis in vitro and in vivo. Together, these findings identify novel cross talk between autophagy and apoptosis, wherein targeting SQSTM1/p62 converts cytoprotective autophagy to an inefficient form due to cargo loading failure, leading to NBK/Bik accumulation, which triggers apoptosis.
机译：在选择性自噬中，衔接蛋白SQSTM1 / p62在识别/装载货物（例如折叠的蛋白）到自噬小体中以溶酶体降解中起关键作用。在这里我们报告，虽然SQSTM1 / p62水平在自噬过程中以时间依赖性的方式波动，但Cdk9 / cyclin T1的抑制或敲低在转录上下调了SQSTM1 / p62，但不影响自噬通量。这些干预措施或直接针对SQSTM1 / p62的短发夹RNA（shRNA）导致货物装载失败和自噬效率低下，这是亨廷顿氏病神经元最近描述的现象。这些事件导致仅BH3蛋白NBK / Bik在内质网（ER）膜上积聚，最有可能是通过阻断NBK / Bik的负载和自噬降解，最终导致细胞凋亡。尽管通过氯喹（CQ）或Lamp2 shRNA破坏远端自噬事件（例如，自噬体成熟）进一步增强了NBK / Bik的上调，但通过抑制自噬启动（例如，通过靶向Ulk1，beclin-1的shRNA的遗传抑制），NBK / Bik的上调作用进一步减弱，或Atg5或药理学上使用3-甲基腺嘌呤[3-MA]或spautin-1），认为NBK / Bik积累源自效率低下的自噬。最终，NBK / Bik敲除显着减弱了体外和体外的凋亡。在一起，这些发现确定了自噬和细胞凋亡之间的新型串扰，其中靶向SQSTM1 / p62由于货物装载失败而将细胞保护性自噬转化为无效形式，导致NBK / Bik积聚，从而触发细胞凋亡。

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