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ZNF322A-mediated protein phosphorylation induces autophagosome formation through modulation of IRS1-AKT glucose uptake and HSP-elicited UPR in lung cancer.
Journal of Biomedical Science ( IF 9.0 ) Pub Date : 2020-06-23 , DOI: 10.1186/s12929-020-00668-5
Chantal Hoi Yin Cheung , Chia-Lang Hsu , Tsai-Yu Lin , Wei-Ting Chen , Yi-Ching Wang , Hsuan-Cheng Huang , Hsueh-Fen Juan

ZNF322A is an oncogenic transcription factor that belongs to the Cys2His2-type zinc-finger protein family. Accumulating evidence suggests that ZNF322A may contribute to the tumorigenesis of lung cancer, however, the ZNF322A-mediated downstream signaling pathways remain unknown. To uncover ZNF322A-mediated functional network, we applied phosphopeptide enrichment and isobaric labeling strategies with mass spectrometry-based proteomics using A549 lung cancer cells, and analyzed the differentially expressed proteins of phosphoproteomic and proteomic profiles to determine ZNF322A-modulated pathways. ZNF322A highlighted a previously unidentified insulin signaling, heat stress, and signal attenuation at the post-translational level. Consistently, protein-phosphoprotein-kinase interaction network analysis revealed phosphorylation of IRS1 and HSP27 were altered upon ZNF322A-silenced lung cancer cells. Thus, we further investigated the molecular regulation of ZNF322A, and found the inhibitory transcriptional regulation of ZNF322A on PIM3, which was able to phosphorylate IRS1 at serine1101 in order to manipulate glucose uptake via the PI3K/AKT/mTOR signaling pathway. Moreover, ZNF322A also affects the unfolded protein response by phosphorylation of HSP27S82 and eIF2aS51, and triggers autophagosome formation in lung cancer cells. These findings not only give new information about the molecular regulation of the cellular proteins through ZNF322A at the post-translational level, but also provides a resource for the study of lung cancer therapy.

中文翻译:

ZNF322A介导的蛋白磷酸化通过调节IRS1-AKT葡萄糖摄取和HSP诱导的UPR诱导肺癌自噬体形成。

ZNF322A是一种致癌转录因子,属于Cys2His2型锌指蛋白家族。越来越多的证据表明ZNF322A可能有助于肺癌的肿瘤发生,但是ZNF322A介导的下游信号通路仍然未知。为了揭示ZNF322A介导的功能网络,我们应用了基于A549肺癌细胞的基于质谱的蛋白质组学进行磷酸肽富集和等压标记策略,并分析了磷酸化蛋白质组学和蛋白质组学谱的差异表达蛋白,以确定ZNF322A调控的途径。ZNF322A在翻译后水平突出显示了以前未确定的胰岛素信号传导,热应激和信号衰减。一致地,蛋白-磷酸蛋白-激酶相互作用网络分析表明,在ZNF322A沉默的肺癌细胞中,IRS1和HSP27的磷酸化发生了改变。因此,我们进一步研究了ZNF322A的分子调控,并发现ZNF322A在PIM3上的抑制性转录调控,该PIM3能够在serine1101上磷酸化IRS1,从而通过PI3K / AKT / mTOR信号通路控制葡萄糖的摄取。此外,ZNF322A还通过HSP27S82和eIF2aS51的磷酸化影响未折叠的蛋白质反应,并触发肺癌细胞中自噬体的形成。这些发现不仅在翻译后水平上提供了有关通过ZNF322A对细胞蛋白进行分子调控的新信息,而且还为肺癌治疗的研究提供了资源。我们进一步研究了ZNF322A的分子调控,并发现ZNF322A对PIM3的抑制转录调控,该PIM3能够在serine1101处磷酸化IRS1,从而通过PI3K / AKT / mTOR信号通路控制葡萄糖的摄取。此外,ZNF322A还通过HSP27S82和eIF2aS51的磷酸化影响未折叠的蛋白质反应,并触发肺癌细胞中自噬体的形成。这些发现不仅在翻译后水平上提供了有关通过ZNF322A对细胞蛋白质进行分子调控的新信息,而且为肺癌治疗的研究提供了资源。我们进一步研究了ZNF322A的分子调控,并发现ZNF322A对PIM3的抑制转录调控,该PIM3能够在serine1101处磷酸化IRS1,从而通过PI3K / AKT / mTOR信号通路控制葡萄糖的摄取。此外,ZNF322A还通过HSP27S82和eIF2aS51的磷酸化影响未折叠的蛋白质反应,并触发肺癌细胞中自噬体的形成。这些发现不仅在翻译后水平上提供了有关通过ZNF322A对细胞蛋白进行分子调控的新信息,而且还为肺癌治疗的研究提供了资源。它能够在serine1101处使IRS1磷酸化,以便通过PI3K / AKT / mTOR信号传导途径控制葡萄糖的摄取。此外,ZNF322A还通过HSP27S82和eIF2aS51的磷酸化影响未折叠的蛋白质反应,并触发肺癌细胞中自噬体的形成。这些发现不仅在翻译后水平上提供了有关通过ZNF322A对细胞蛋白进行分子调控的新信息,而且还为肺癌治疗的研究提供了资源。它能够在serine1101处使IRS1磷酸化,以便通过PI3K / AKT / mTOR信号传导途径控制葡萄糖的摄取。此外,ZNF322A还通过HSP27S82和eIF2aS51的磷酸化影响未折叠的蛋白质反应,并触发肺癌细胞中自噬体的形成。这些发现不仅在翻译后水平上提供了有关通过ZNF322A对细胞蛋白进行分子调控的新信息,而且还为肺癌治疗的研究提供了资源。
更新日期:2020-07-01
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