The ion channel CALHM6 controls bacterial infection-induced cellular cross-talk at the immunological synapse.
The ion channel CALHM6 controls bacterial infection-induced cellular cross-talk at the immunological synapse.
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DOI：
10.15252/embj.2022111450
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发表时间：
2023-04-03
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钙稳态调节蛋白（CALHM）家族的膜离子通道通过释放三磷酸腺苷（ATP）促进神经元突触处的细胞间相互交流，在此过程中ATP发挥着神经递质的作用。CALHM6是CALHM家族中唯一在免疫细胞中高表达的成员，它与自然杀伤（NK）细胞抗肿瘤活性的诱导有关。然而，其作用机制以及在免疫系统中更广泛的功能仍不明确。在此，我们培育出了Calhm6基因敲除小鼠，并发现CALHM6对体内单核细胞增生李斯特菌感染早期固有免疫调控至关重要。我们发现，病原体衍生的信号可使巨噬细胞中CALHM6表达上调，且CALHM6会从细胞内区室重新定位至巨噬细胞 - NK细胞突触处，从而促进ATP释放并调控NK细胞激活的动力学过程。抗炎细胞因子会终止CALHM6的表达。当在非洲爪蟾卵母细胞的质膜中表达时，CALHM6会形成离子通道，通道的开启由一个保守的酸性残基E119控制。在哺乳动物细胞中，CALHM6定位于细胞内区室。我们的研究结果有助于理解免疫细胞间类似神经递质的信号交换，这种交换可精准调节固有免疫反应的时机。
CALHM6通过调节免疫突触处的ATP释放来控制NK细胞激活，从而精准调节固有免疫反应的时机。
Membrane ion channels of the calcium homeostasis modulator (CALHM) family promote cell–cell crosstalk at neuronal synapses via ATP release, where ATP acts as a neurotransmitter. CALHM6, the only CALHM highly expressed in immune cells, has been linked to the induction of natural killer (NK) cell anti‐tumour activity. However, its mechanism of action and broader functions in the immune system remain unclear. Here, we generated Calhm6 −/− mice and report that CALHM6 is important for the regulation of the early innate control of Listeria monocytogenes infection in vivo. We find that CALHM6 is upregulated in macrophages by pathogen‐derived signals and that it relocates from the intracellular compartment to the macrophage‐NK cell synapse, facilitating ATP release and controlling the kinetics of NK cell activation. Anti‐inflammatory cytokines terminate CALHM6 expression. CALHM6 forms an ion channel when expressed in the plasma membrane of Xenopus oocytes, where channel opening is controlled by a conserved acidic residue, E119. In mammalian cells, CALHM6 is localised to intracellular compartments. Our results contribute to the understanding of neurotransmitter‐like signal exchange between immune cells that fine‐tunes the timing of innate immune responses. CALHM6 fine‐tunes the timing of innate immune responses by regulating ATP release at the immunological synapse to control NK cell activation.