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Autophagy, Jul 02 2024, | https://doi.org/10.1080/15548627.2024.2374692 Metabolic stress induces a double-positive feedback loop between AMPK and SQSTM1/p62 conferring dual activation of AMPK and NFE2L2/NRF2 to synergize antioxidant defense

Eun-Ji Choi ^1,2, Hyun-Taek Oh^1,3, Seon-Hyeong Lee⁴, Chen-Song Zhang ⁵, Mengqi Li⁵, Soo-Youl Kim ⁴, Sunghyouk Park⁶, Tong-Shin Chang¹, Byung-Hoon Lee ¹, Sheng-Cai Lin ⁵, Sang-Min Jeon ^1,2,3

¹Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul, Korea.

²College of Pharmacy, Ajou University, Suwon, Gyeonggi-do, Korea.

³Department of BioHealth Regulatory Science, Graduate School of Ajou University, Suwon, Gyeonggi-do, Korea.

⁴Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea.

⁵State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Fujian, China.

⁶Natural Products Research Institute and College of Pharmacy, Seoul National University, Seoul, Korea.

Correspondence: Sang-Min Jeon

Abstract

Co-occurring mutations in KEAP1 in STK11/LKB1-mutant NSCLC activate NFE2L2/NRF2 to compensate for the loss of STK11-AMPK activity during metabolic adaptation. Characterizing the regulatory crosstalk between the STK11-AMPK and KEAP1-NFE2L2 pathways during metabolic stress is crucial for understanding the implications of co-occurring mutations. Here, we found that metabolic stress increased the expression and phosphorylation of SQSTM1/p62, which is essential for the activation of NFE2L2 and AMPK, synergizing antioxidant defense and tumor growth. The SQSTM1-driven dual activation of NFE2L2 and AMPK was achieved by inducing macroautophagic/autophagic degradation of KEAP1 and facilitating the AXIN-STK11-AMPK complex formation on the lysosomal membrane, respectively. In contrast, the STK11-AMPK activity was also required for metabolic stress-induced expression and phosphorylation of SQSTM1, suggesting a double-positive feedback loop between AMPK and SQSTM1. Mechanistically, SQSTM1 expression was increased by the PPP2/PP2A-dependent dephosphorylation of TFEB and TFE3, which was induced by the lysosomal deacidification caused by low glucose metabolism and AMPK-dependent proton reduction. Furthermore, SQSTM1 phosphorylation was increased by MAP3K7/TAK1, which was activated by ROS and pH-dependent secretion of lysosomal Ca ²⁺. Importantly, phosphorylation of SQSTM1 at S24 and S226 was critical for the activation of AMPK and NFE2L2. Notably, the effects caused by metabolic stress were abrogated by the protons provided by lactic acid. Collectively, our data reveal a novel double-positive feedback loop between AMPK and SQSTM1 leading to the dual activation of AMPK and NFE2L2, potentially explaining why co-occurring mutations in STK11 and KEAP1 happen and providing promising therapeutic strategies for lung cancer.

논문정보

형식Research article
게재일2024년 07월 (BRIC 등록일 2024-07-03)
연구진국내 연구진
분야 의약학 > 약학

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