首页|Wip1 inhibits neutrophil extracellular traps to promote abscess formation in mice by directly dephosphorylating Coronin-1a

Wip1 inhibits neutrophil extracellular traps to promote abscess formation in mice by directly dephosphorylating Coronin-1a

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Neutrophil extracellular traps(NETs)participate in the rapid inhibition and clearance of pathogens during infection;however,the molecular regulation of NET formation remains poorly understood.In the current study,we found that inhibition of the wild-type p53-induced phosphatase 1(Wip1)significantly suppressed the activity of Staphylococcus aureus(S.aureus)and accelerated abscess healing in S.aureus-induced abscess model mice by enhancing NET formation.A Wip1 inhibitor significantly enhanced NET formation in mouse and human neutrophils in vitro.High-resolution mass spectrometry and biochemical assays demonstrated that Coro1a is a substrate of Wip1.Further experiments also revealed that Wip1 preferentially and directly interacts with phosphorylated Coro1a than compared to unphosphorylated inactivated Coro1a.The phosphorylated Ser426 site of Coro1a and the 28-90 aa domain of Wip1 are essential for the direct interaction of Coro1a and Wip1 and for Wip1 dephosphorylation of p-Coro1a Ser426.Wip1 deletion or inhibition in neutrophils significantly upregulated the phosphorylation of Coro1a-Ser426,which activated phospholipase C and subsequently the calcium pathway,the latter of which promoted NET formation after infection or lipopolysaccharide stimulation.This study revealed Coro1a to be a novel substrate of Wip1 and showed that Wip1 is a negative regulator of NET formation during infection.These results support the potential application of Wip1 inhibitors to treat bacterial infections.

Wild-type p53-induced phosphatase 1(Wip1)Coro1aCalcium pathwayNeutrophilsNeutrophil extracellular trap(NET)Abscess

Yifang Chen、Chenxu Zhao、Han Guo、Weilong Zou、Zhaoqi Zhang、Dong Wei、Hezhe Lu、Lianfeng Zhang、Yong Zhao

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State Key Laboratory of Membrane Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing,China

University of Chinese Academy of Sciences,Beijing,China

Beijing Institute for Stem Cell and Regeneration,Beijing,China

Department of Hepatobiliary Surgery,The Affiliated Hospital of Guizhou Medical University,Guiyang,Guizhou,China

Institute of Laboratory Animal Science,Chinese Academy of Medical Sciences,Beijing,China

Shenzhen Institute of Advanced Technology,Chinese Academy of Sciences,Shenzhen,China

Key Laboratory of Human Diseases Comparative Medicine,Ministry of Health

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National Natural Science Foundation for General and Key ProgramsNational Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaNational Key Research and Development Program of ChinaKnowledge Innovation Program of the Chinese Academy of SciencesDoctoral Research Foundation Project of Affiliated Hospital of Guizhou Medical University

319300412017YFA01050022017YFA01044012017YFA0104402XDA16030301gyfybsky-2022-1

2023

10.1038/s41423-023-01057-2

中国免疫学杂志(英文版)
中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI
影响因子：0.731
ISSN：1672-7681
年,卷(期)：2023.20(8)
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