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喜报:恭喜我司再创佳绩,SCI文献44.09分！
点击次数：437发布时间：2023/8/2
Mannose antagonizes GSDME-mediated pyroptosis through
AMPK activated by metabolite GlcNAc-6P
Yuan-li Ai1,4, Wei-jia Wang1,4✉, Fan-jian Liu1,4, Wei Fang1,4, Hang-zi Chen 1 , Liu-zheng Wu1 , Xuehui Hong2✉, Yuekun Zhu3 ,
Ci-xiong Zhang1 , Long-yu Liu1 , Wen-bin Hong 1 , Bo Zhou1 , Qi-tao Chen1 and Qiao Wu 1✉
© The Author(s) 2023
Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis
is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by
activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway
increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK
phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced
GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further
confirmed in AMPK knockout ａnd GSDMET6E or GSDMET6A knock-in mice. In mouse primary cancer models, mannose administration
suppressed pyroptosis in small intestine ａnd kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing
antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who
received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis
through GlcNAc-6P-mediated activation of AMPK, ａnd suggests the utility of mannose supplementation in alleviating
chemotherapy-induced side effects in clinic applications.
Cell Research (2023) 0:1–19; https://doi.org/10.1038/s41422-023-00848-6
INTRODUCTION
The ubiquitous AMP-activated protein kinase (AMPK), a hetero
trimeric protein complex consisting of catalytic subunit α and
regulatory subunits β and γ, is a key sensor in cellular energy
metabolism.1,2 The canonical adenine nucleotide-dependent
AMPK activation is induced by cellular energy shortage due to
the intracellular depletion of ATP ａnd increase of AMP/ADP levels.2
AMP/ADP binds the AMPK γ subunits, triggering a conformational
change to enable the phosphorylation of the α subunit at Thr172
by either LKB1 or CaMKK2, two upstream kinases. AMPK can also
be activated through compound-dependent noncanonical path
ways.3 For example, compound A-769662 enables the allosteric
activation of AMPK ａnd inhibits the dephosphorylation of AMPK at
Thr172 with its binding in between catalytic subunit α and
regulatory subunit β. 4 It was recently demonstrated that a
decrease in cellular fructose-1,6-bisphosphate (FBP) also triggered
the activation of AMPK through the LKB1-AMPK-Axin signaling
pathway on the surface of the lysosome,5 suggesting that it was a
metabolite that functioned as a signaling molecule to regulate the
AMPK activity.
As a metabolic hub, AMPK promotes ATP-generating catabolic
processes ａnd inhibits ATP-consuming anabolic processes by
phosphorylating a myriad of downstream targets.1 Moreover,
AMPK has also been linked to many non-metabolic processes,
such as those that control the cell fate, including auhagy,6–10
apoptosis10,11 and ferroptosis.12 AMPK abolishes ferroptosis due to
ischemia-reperfusion injury by enhancing acetyl-CoA carboxylase
(ACC) phosphorylation ａnd inhibiting polyunsaturated fatty acid
(PUFA) generation.12 A recent study showed that AMPK protects
against liver cell death by phosphorylating proapoptotic caspase-6
in nonalcoholic steatohepatitis (NASH),11 suggesting the inhibitory
effect of AMPK on apoptosis. However, compared to the canonical
function of AMPK for metabolic homeostasis, novel substrates of
AMPK that determine cell fate ａnd the underlying mechanism
remain under investigated.
Pyroptosis is a newly identified form of regulatory cell death. It
is characterized by the cleavage of N-terminal segments of
gasdermin family members, including GSDMA, GSDMB, GSDMC,
GSDMD, ａnd GSDME. Those cleaved N-terminal fragments
translocate to ａnd perforate the cell membrane, resulting in cell
swelling ａnd cell death.13 Our previous study demonstrated that
although treatment with some clinical ROS-inducing drugs alone,
such as sulfasalazine, could not induce pyroptosis in melanoma
cells, co-treatment with iron ａnd sulfasalazine significantly
increased the occurrence of GSDME-mediated pyroptosis, in
which iron acts as a sensitizer for pyroptotic induction of
melanoma cells.14 Since melanoma cells are often resistant to
apoptosis, this iron-dependent mechanism of pyroptosis induction
Received: 30 November 2022 Accepted: 25 June 2023
1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. 2 Department of Gastrointestinal Surgery, Zhongshan Hospital of
Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China. 3 Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University,
Harbin, Heilongjiang, China. 4 These authors contributed equally: Yuan-li Ai, Wei-jia Wang, Fan-jian Liu, Wei Fang. ✉email: wangwj@xmu.edu.cn; hongxu@xmu.edu.cn;
qiaow@xmu.edu.cn
Received: 30 November 2022 Accepted: 25 June 2023
