State Key Laboratory of Molecular Oncology, National Cancer center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, China.
Signal Transduct Target Ther. 2021 Apr 16;6(1):152. doi: 10.1038/s41392-021-00543-1.
Autophagy is the main degradation pathway to eliminate long-lived and aggregated proteins, aged or malfunctioning organelles, which is essential for the intracellular homeostasis and prevention of malignant transformation. Although the processes of autophagosome biogenesis have been well illuminated, the mechanism of autophagosome transport remains largely unclear. In this study, we demonstrated that the ninein-like protein (Nlp), a well-characterized centrosomal associated protein, was able to modulate autophagosome transport and facilitate autophagy. During autophagy, Nlp colocalized with autophagosomes and physically interacted with autophagosome marker LC3, autophagosome sorting protein Rab7 and its downstream effector FYCO1. Interestingly, Nlp enhanced the interaction between Rab7 and FYCO1, thus accelerated autophagic flux and the formation of autophagolysosomes. Furthermore, compared to the wild-type mice, NLP deficient mice treated with chemical agent DMBA were prone to increased incidence of hepatomegaly and liver cancer, which were tight associated with the hepatic autophagic defect. Taken together, our findings provide a new insight for the first time that the well-known centrosomal protein Nlp is also a new regulator of autophagy, which promotes the interaction of Rab7 and FYCO1 and facilitates the formation of autophagolysosome.
自噬是消除长寿和聚集蛋白、衰老或功能失调细胞器的主要降解途径，对于细胞内平衡和防止恶性转化至关重要。虽然自噬体生物发生的过程已经得到很好的阐明，但自噬体运输的机制在很大程度上仍不清楚。在本研究中，我们证明了九肽样蛋白（Nlp），一种特征明确的中心体相关蛋白，能够调节自噬体运输并促进自噬。在自噬过程中，Nlp 与自噬体共定位，并与自噬体标记物 LC3、自噬体分选蛋白 Rab7 及其下游效应因子 FYCO1 发生物理相互作用。有趣的是，Nlp 增强了 Rab7 和 FYCO1 之间的相互作用，从而加速了自噬流和自噬溶酶体的形成。此外，与野生型小鼠相比，用化学试剂 DMBA 处理的 NLP 缺陷型小鼠更容易发生肝肿大和肝癌，这与肝脏自噬缺陷密切相关。总之，我们的研究结果首次提供了一个新的见解，即著名的中心体蛋白 Nlp 也是自噬的一个新调节剂，它促进了 Rab7 和 FYCO1 的相互作用，并促进了自噬溶酶体的形成。
