Cells (May 2024)

Immunoglobulin Superfamily Containing Leucine-Rich Repeat (ISLR) Serves as a Redox Sensor That Modulates Antioxidant Capacity by Suppressing Pyruvate Kinase Isozyme M2 Activity

  • Tongtong Wang,
  • Meijing Chen,
  • Yang Su,
  • Yuying Zhang,
  • Chang Liu,
  • Miaomiao Lan,
  • Lei Li,
  • Fan Liu,
  • Na Li,
  • Yingying Yu,
  • Lei Xiong,
  • Kun Wang,
  • Jin Liu,
  • Qing Xu,
  • Yue Hu,
  • Yuxin Jia,
  • Yuxin Cao,
  • Jingwen Pan,
  • Qingyong Meng

DOI
https://doi.org/10.3390/cells13100838
Journal volume & issue
Vol. 13, no. 10
p. 838

Abstract

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Cells defend against oxidative stress by enhancing antioxidant capacity, including stress-activated metabolic alterations, but the underlying intracellular signaling mechanisms remain unclear. This paper reports that immunoglobulin superfamily containing leucine-rich repeat (ISLR) functions as a redox sensor that responds to reactive oxygen species (ROS) stimulation and modulates the antioxidant capacity by suppressing pyruvate kinase isozyme M2 (PKM2) activity. Following oxidative stress, ISLR perceives ROS stimulation through its cysteine residue 19, and rapidly degrades in the autophagy–lysosome pathway. The downregulated ISLR enhances the antioxidant capacity by promoting the tetramerization of PKM2, and then enhancing the pyruvate kinase activity, PKM2-mediated glycolysis is crucial to the ISLR-mediated antioxidant capacity. In addition, our results demonstrated that, in triple-negative breast cancer, cisplatin treatment reduced the level of ISLR, and PKM2 inhibition sensitizes tumors to cisplatin by enhancing ROS production; and argued that PKM2 inhibition can synergize with cisplatin to limit tumor growth. Our results demonstrate a molecular mechanism by which cells respond to oxidative stress and modulate the redox balance.

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