A stress response p38 MAP kinase inhibitor SB202190 promoted TFEB/TFE3-dependent autophagy and lysosomal biogenesis independent of p38

Publication date: Available online 28 January 2020Source: Redox BiologyAuthor(s): Chuanbin Yang, Zhou Zhu, Benjamin Chun-Kit Tong, Ashok Iyaswamy, Wen-Jian Xie, Yu Zhu, Sravan Gopalkrishnashetty Sreenivasmurthy, Krishnamoorthi Senthilkumar, King-Ho Cheung, Ju-Xian Song, Hong-Jie Zhang, Min LiAbstractTFEB (transcription factor EB) and TFE3 (transcription factor E3) are “master regulators” of autophagy and lysosomal biogenesis. The stress response p38 mitogen-activated protein (MAP) kinases affects multiple intracellular responses including inflammation, cell growth, differentiation, cell death, senescence, tumorigenesis, and autophagy. Small molecule p38 MAP kinase inhibitors such as SB202190 are widely used in dissection of related signal transduction mechanisms including redox biology and autophagy. Here, we initially aimed to investigate the links between p38 MAP kinase and TFEB/TFE3-mediated autophagy and lysosomal biogenesis. Unexpectedly, we found that only SB202190, rather than several other p38 inhibitors, promotes TFEB and TFE3 to translocate from the cytosol into the nucleus and subsequently enhances autophagy and lysosomal biogenesis. In addition, siRNA-mediated Tfeb and Tfe3 knockdown effectively attenuated SB202190-induced gene expression and lysosomal biogenesis. Mechanistical studies showed that TFEB and TFE3 activation in response to SB202190 is dependent on PPP3/calcineurin rather than on the inhibition of p38 or MTOR signaling, the main pathway for regula...

Source: Redox Biology - January 29, 2020 Category: Biology Source Type: research