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Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase.
Lu, Jing; Liu, Xue; Li, Xinghua; Li, Hongyan; Shi, Liwa; Xia, Xin; He, Bai-Liang; Meyer, Thomas F; Li, Xiaofeng; Sun, Hongzhe; Yang, Xinming.
Afiliação
  • Lu J; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • Liu X; Department of Gastroenterology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • Li X; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • Li H; Department of Chemistry, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Shi L; Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • Xia X; Department of Infectious Diseases, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • He BL; Department of Chemistry, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Meyer TF; Chinese Academy of Sciences-The University of Hong Kong Joint Laboratory of Metallomics on Health and Environment, The University of Hong Kong, Hong Kong Special Administrative Region, China.
  • Li X; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • Sun H; Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
  • Yang X; Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
Proc Natl Acad Sci U S A ; 121(4): e2311630121, 2024 Jan 23.
Article em En | MEDLINE | ID: mdl-38232278
ABSTRACT
Copper is an essential trace element for the human body, and its requirement for optimistic immune functions has been recognized for decades. How copper is involved in the innate immune pathway, however, remains to be clarified. Here, we report that copper serves as a signal molecule to regulate the kinase activity of alpha-kinase 1 (ALPK1), a cytosolic pattern-recognition receptor (PRR), and therefore promotes host cell defense against bacterial infection. We show that in response to infection, host cells actively accumulate copper in the cytosol, and the accumulated cytosolic copper enhances host cell defense against evading pathogens, including intracellular and, unexpectedly, extracellular bacteria. Subsequently, we demonstrate that copper activates the innate immune pathway of host cells in an ALPK1-dependent manner. Further mechanistic studies reveal that copper binds to ALPK1 directly and is essential for the kinase activity of this cytosolic PRR. Moreover, the binding of copper to ALPK1 enhances the sensitivity of ALPK1 to the bacterial metabolite ADP-heptose and eventually prompts host cells to elicit an enhanced immune response during bacterial infection. Finally, using a zebrafish in vivo model, we show that a copper-treated host shows an increased production of proinflammatory cytokines, enhanced recruitment of phagosome cells, and promoted bacterial clearance. Our findings uncover a previously unrecognized role of copper in the modulation of host innate immune response against bacterial pathogens and advance our knowledge on the cross talk between cytosolic copper homeostasis and immune system.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Infecções Bacterianas / Cobre Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Infecções Bacterianas / Cobre Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2024 Tipo de documento: Article País de afiliação: China