Copper regulates the host innate immune response against bacterial infection via activation of ALPK1 kinase

• 成果类型: Article
• 署名作者: Lu, Jing; Liu, Xue; Li, Xinghua; Li, Hongyan; Shi, Liwa; Xia, Xin; He, Bai-liang; Meyer, Thomas F.; Li, Xiaofeng; Sun, Hongzhe; Yang, Xinming
• 署名单位: Sun Yat Sen University; Sun Yat Sen University; University of Hong Kong; Sun Yat Sen University; Sun Yat Sen University; University of Hong Kong; Max Planck Society; University of Kiel; Schleswig Holstein University Hospital
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10959
• DOI: 10.1073/pnas.2311630121
• 发表日期: 2024-01-23
• 关键词: pattern-recognition receptors; inhibition; sensor

摘要

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.