AKR1C1 connects autophagy and oxidative stress by interacting with SQSTM1 in a catalytic-independent manner
AKR1C1 connects autophagy and oxidative stress by interacting with SQSTM1 in a catalytic-independent manner
复制标题
DOI：
10.1038/s41401-021-00673-w
复制
发表时间：
2021-05-20
影响因子：
8.2
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Chang, Lin-lin;Li, Yue-kang;Yang, Bo
靶向自噬可能是一种有前途的抗癌策略;然而，自噬在癌症发展和恶性肿瘤中的双重作用仍不清楚。NSCLC（非小细胞肺癌）细胞含有高水平的SQSTM 1（隔离体1），自噬受体对自噬的双重作用至关重要。因此，对SQSTM 1调节的机制见解可能指向治疗NSCLC的更好方法。在本文中，我们使用多种自噬通量模型和自噬读数来显示在NSCLC中高度表达的醛酮还原酶家族1成员C1（AKR 1C 1）通过以催化非依赖性方式直接结合SQSTM 1来促进自噬。这种相互作用可能会加强活性氧（ROS），重要的自噬诱导剂。进一步的机制研究表明，AKR 1C 1与SQSTM 1相互作用以增强SQSTM 1寡聚化，从而有助于SQSTM 1对结合货物的亲和力。总的来说，我们的数据揭示了AKR 1C 1与SQSTM 1相互作用并促进自噬的催化独立作用。所有这些发现不仅揭示了AKR 1C 1在自噬过程中的新功能作用，而且表明调节AKR 1C 1-SQSTM 1相互作用可能是靶向自噬的新策略。
Targeting autophagy might be a promising anticancer strategy; however, the dual roles of autophagy in cancer development and malignancy remain unclear. NSCLC (non-small cell lung cancer) cells harbour high levels of SQSTM1 (sequestosome 1), the autophagy receptor that is critical for the dual roles of autophagy. Therefore, mechanistic insights into SQSTM1 modulation may point towards better approaches to treat NSCLC. Herein, we used multiple autophagy flux models and autophagy readouts to show that aldo-keto reductase family 1 member C1 (AKR1C1), which is highly expressed in NSCLC, promotes autophagy by directly binding to SQSTM1 in a catalytic-independent manner. This interaction may be strengthened by reactive oxygen species (ROS), important autophagy inducers. Further mechanistic research demonstrated that AKR1C1 interacts with SQSTM1 to augment SQSTM1 oligomerization, contributing to the SQSTM1 affinity for binding cargo. Collectively, our data reveal a catalytic-independent role of AKR1C1 for interacting with SQSTM1 and promoting autophagy. All these findings not only reveal a novel functional role of AKR1C1 in the autophagy process but also indicate that modulation of the AKR1C1-SQSTM1 interaction may be a new strategy for targeting autophagy.