Staff and Researcher Publications
Language
English
Publication Date
11-1-2024
Journal
Autophagy
DOI
10.1080/15548627.2024.2374692
PMID
38953310
PMCID
PMC11572134
PubMedCentral® Posted Date
7-2-2024
PubMedCentral® Full Text Version
Post-print
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 Ca2+. 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.Abbreviations: AMPK: AMP-activated protein kinase; BAF1: bafilomycin A1; ConA: concanamycin A; DOX: doxycycline; IP: immunoprecipitation; KEAP1: kelch like ECH associated protein 1; LN: low nutrient; MAP3K7/TAK1: mitogen-activated protein kinase kinase kinase 7; MCOLN1/TRPML1: mucolipin TRP cation channel 1; MEFs: mouse embryonic fibroblasts; MTORC1: mechanistic target of rapamycin kinase complex 1; NAC: N-acetylcysteine; NFE2L2/NRF2: NFE2 like bZIP transcription factor 2; NSCLC: non-small cell lung cancer; PRKAA/AMPKα: protein kinase AMP-activated catalytic subunit alpha; PPP2/PP2A: protein phosphatase 2; ROS: reactive oxygen species; PPP3/calcineurin: protein phosphatase 3; RPS6KB1/p70S6K: ribosomal protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; TCL: total cell lysate; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3; V-ATPase: vacuolar-type H+-translocating ATPase.
Keywords
Mutation, Stress, Physiological, Feedback, Physiological, Antioxidants, Cell Line, Tumor, Mice, Inbred BALB C, Humans, Male, Animals, Mice, Xenograft Model Antitumor Assays, Sequestosome-1 Protein, AMP-Activated Protein Kinases, NF-E2-Related Factor 2, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Kelch-Like ECH-Associated Protein 1, AMP-Activated Protein Kinase Kinases, Tumor Microenvironment, Cell Survival, Oxidative Stress, AXIN, KEAP1, lysosomal stress, metabolic stress, oxidative stress, STK11/LKB1
Published Open-Access
yes
Recommended Citation
Choi, Eun-Ji; Oh, Hyun-Taek; Lee, Seon-Hyeong; et al., "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" (2024). Staff and Researcher Publications. 62.
https://digitalcommons.library.tmc.edu/clinic_pub/62
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