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<p>Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 6 (NLRP6) is a pattern recognition receptor that is highly expressed in microglia and forms a cytosolic inflammasome to aggravate neuroinflammation and neuronal injury during ischemic stroke. However, the post-translational mechanisms regulating the NLRP6 inflammasome activation are not well characterized. Herein, we demonstrated that the phosphorylation of NLRP6 was markedly increased in response to cerebral ischemia and was closely associated with NLRP6 inflammasome function. Serine 27 (Ser27) was identified as a conserved phosphorylation site in NLRP6, and NLRP6 inflammasome activity was tightly regulated by phosphorylation at this site. Moreover, the oligomerization and subsequent inflammasome assembly and activation of NLRP6 were positively regulated by Ser27 phosphorylation. Phenotypically, dephosphorylation at the Ser27 site blocked NLRP6 inflammasome activation in ischemic stroke, drastically reducing inflammasome-related neuroinflammation and neurological injury in vitro and in vivo. Our findings demonstrate a pivotal mechanism regulating NLRP6 inflammasome activation in ischemic stroke and provide evidence for the therapeutic targeting of NLRP6 Ser27 phosphorylation.</p>

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Phosphorylation of NLRP6 at Serine 27 site is critical for NLRP6 inflammasome activation and neurological impairment in ischemic stroke

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月28日

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  • Junyi Tan,
  • Meng Wang,
  • Keli Huang,
  • Mao Xie,
  • Yaling Zheng,
  • Jing Luo,
  • Jiutang Tang,
  • Xuan Zhai,
  • Qi He,
  • Jing Zhao

摘要

Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 6 (NLRP6) is a pattern recognition receptor that is highly expressed in microglia and forms a cytosolic inflammasome to aggravate neuroinflammation and neuronal injury during ischemic stroke. However, the post-translational mechanisms regulating the NLRP6 inflammasome activation are not well characterized. Herein, we demonstrated that the phosphorylation of NLRP6 was markedly increased in response to cerebral ischemia and was closely associated with NLRP6 inflammasome function. Serine 27 (Ser27) was identified as a conserved phosphorylation site in NLRP6, and NLRP6 inflammasome activity was tightly regulated by phosphorylation at this site. Moreover, the oligomerization and subsequent inflammasome assembly and activation of NLRP6 were positively regulated by Ser27 phosphorylation. Phenotypically, dephosphorylation at the Ser27 site blocked NLRP6 inflammasome activation in ischemic stroke, drastically reducing inflammasome-related neuroinflammation and neurological injury in vitro and in vivo. Our findings demonstrate a pivotal mechanism regulating NLRP6 inflammasome activation in ischemic stroke and provide evidence for the therapeutic targeting of NLRP6 Ser27 phosphorylation.