TY - JOUR
T1 - Gasdermin D-mediated pyroptosis is regulated by AMPK-mediated phosphorylation in tumor cells
AU - Chu, Xiufeng
AU - Xiao, Xiang
AU - Wang, Guangchuan
AU - Uosef, Ahmed
AU - Lou, Xiaohua
AU - Arnold, Preston
AU - Wang, Yixuan
AU - Kong, Gangcheng
AU - Wen, Mou
AU - Minze, Laurie J.
AU - Li, Xian C.
N1 - Funding Information:
This project was supported by National Institutes of Health grants (R01AI080779 and R01A1155488). BCM Mass Spectrometry Proteomics Core is supported by the Dan L. Duncan Comprehensive Cancer Center NIH award (P30 CA125123), CPRIT Core Facility Award (RP170005).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/7
Y1 - 2023/7
N2 - Gasdermin D (GSDMD) is a critical mediator of pyroptosis, which consists of a N-terminal pore-forming domain and a C-terminal autoinhibitory domain. Its cytolytic activity is sequestered by the intramolecular autoinhibitory mechanism. Upon caspase-1/11 mediated cleavage of GSDMD, the N-terminal pore-forming domain (GD-NT) is released to mediate pyroptosis. However, it remains unclear how GD-NT is regulated once it is generated. In the current study, we developed a TetOn system in which GD-NT was selectively induced in tumor cells to explore how the cytolytic activity of GD-NT is regulated. We found that the cytolytic activity of GD-NT was negatively regulated by the AMP-activated protein kinase (AMPK) and AMPK activation rendered tumor cells resistant to GD-NT-mediated pyroptosis. Mechanistically, AMPK phosphorylated GD-NT at the serine 46 (pS46-GD), which altered GD-NT oligomerization and subsequently eliminated its pore-forming ability. In our in vivo tumor model, AMPK-mediated phosphorylation abolished GD-NT-induced anti-tumor activity and resulted in an aggressive tumor growth. Thus, our data demonstrate the critical role of AMPK in negatively regulating the cytolytic activity of GD-NT. Our data also highlight an unexpected link between GSDMD-mediated pyroptosis and the AMPK signaling pathway in certain tumor cells.
AB - Gasdermin D (GSDMD) is a critical mediator of pyroptosis, which consists of a N-terminal pore-forming domain and a C-terminal autoinhibitory domain. Its cytolytic activity is sequestered by the intramolecular autoinhibitory mechanism. Upon caspase-1/11 mediated cleavage of GSDMD, the N-terminal pore-forming domain (GD-NT) is released to mediate pyroptosis. However, it remains unclear how GD-NT is regulated once it is generated. In the current study, we developed a TetOn system in which GD-NT was selectively induced in tumor cells to explore how the cytolytic activity of GD-NT is regulated. We found that the cytolytic activity of GD-NT was negatively regulated by the AMP-activated protein kinase (AMPK) and AMPK activation rendered tumor cells resistant to GD-NT-mediated pyroptosis. Mechanistically, AMPK phosphorylated GD-NT at the serine 46 (pS46-GD), which altered GD-NT oligomerization and subsequently eliminated its pore-forming ability. In our in vivo tumor model, AMPK-mediated phosphorylation abolished GD-NT-induced anti-tumor activity and resulted in an aggressive tumor growth. Thus, our data demonstrate the critical role of AMPK in negatively regulating the cytolytic activity of GD-NT. Our data also highlight an unexpected link between GSDMD-mediated pyroptosis and the AMPK signaling pathway in certain tumor cells.
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U2 - 10.1038/s41419-023-06013-6
DO - 10.1038/s41419-023-06013-6
M3 - Article
C2 - 37495617
AN - SCOPUS:85165876921
SN - 2041-4889
VL - 14
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 7
M1 - 469
ER -