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<p><i>Streptococcus suis</i> (<i>S. suis</i>) induces host cell death and has the ability to invade the blood–brain barrier (BBB). However, <i>S. suis</i>-induced BBB disruption has not been completely elucidated. In this study, we focused on the regulatory role of lysine acetyltransferase 2A (KAT2A) on BBB, which is a key regulator of cell death. We found that <i>S. suis</i> strain SC19 induces cell death in human cerebral microvascular endothelial cell line D3 (hCMEC/D3) by membrane disruption and LDH release. During SC19 infection, KAT2A protein expression was markedly reduced but its mRNA expression was not affected. Further study demonstrated that SC19-induced KAT2A reduction was though ubiquitin–proteasome-mediated protein degradation pathway. KAT2A inhibition using significantly exacerbated SC19-induced cell permeability disruption by transwell infection model. Consistently, KAT2A knockdown and pharmacological inhibition significantly aggravated SC19-induced downregulation of tight junction proteins including ZO-1 and occludin, whereas KAT2A overexpression partially restored their levels. Similarly, KAT2A inhibition aggravated SC19-induced downregulation of ZO-1 in mice brain and increased mice death rate, indicating the protective role of KAT2A on BBB. Mechanistically, KAT2A was found to regulate necroptosis in hCMEC/D3. KAT2A knockdown aggravated necroptosis and upregulated phosphorylation of RIPK1, whereas RIPK1 inhibitor Nec-1 rescued SC19-induced necroptosis, indicating that KAT2A regulates RIPK1-dependent necroptosis during SC19 infection. Furthermore, quantitative proteomic analysis identified a network of putative KAT2A-mediated downstream targets and pathways that contribute to BBB integrity. Collectively, these findings reveal the underlying mechanism by which SC19 disrupts BBB through inducing KAT2A-mediated necroptosis and provide a potential therapeutic target for the treatment of bacterial meningitis.</p>

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Streptococcus suis disrupts the blood–brain barrier through inducing ubiquitin–proteasome-mediated degradation of KAT2A

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月25日

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  • Yuqing Li,
  • Hang Yin,
  • Tao Zhang,
  • Shiqi Lang,
  • Tianning Yang,
  • Zhiwei Li,
  • Lianci Peng,
  • Rendong Fang

摘要

Streptococcus suis (S. suis) induces host cell death and has the ability to invade the blood–brain barrier (BBB). However, S. suis-induced BBB disruption has not been completely elucidated. In this study, we focused on the regulatory role of lysine acetyltransferase 2A (KAT2A) on BBB, which is a key regulator of cell death. We found that S. suis strain SC19 induces cell death in human cerebral microvascular endothelial cell line D3 (hCMEC/D3) by membrane disruption and LDH release. During SC19 infection, KAT2A protein expression was markedly reduced but its mRNA expression was not affected. Further study demonstrated that SC19-induced KAT2A reduction was though ubiquitin–proteasome-mediated protein degradation pathway. KAT2A inhibition using significantly exacerbated SC19-induced cell permeability disruption by transwell infection model. Consistently, KAT2A knockdown and pharmacological inhibition significantly aggravated SC19-induced downregulation of tight junction proteins including ZO-1 and occludin, whereas KAT2A overexpression partially restored their levels. Similarly, KAT2A inhibition aggravated SC19-induced downregulation of ZO-1 in mice brain and increased mice death rate, indicating the protective role of KAT2A on BBB. Mechanistically, KAT2A was found to regulate necroptosis in hCMEC/D3. KAT2A knockdown aggravated necroptosis and upregulated phosphorylation of RIPK1, whereas RIPK1 inhibitor Nec-1 rescued SC19-induced necroptosis, indicating that KAT2A regulates RIPK1-dependent necroptosis during SC19 infection. Furthermore, quantitative proteomic analysis identified a network of putative KAT2A-mediated downstream targets and pathways that contribute to BBB integrity. Collectively, these findings reveal the underlying mechanism by which SC19 disrupts BBB through inducing KAT2A-mediated necroptosis and provide a potential therapeutic target for the treatment of bacterial meningitis.