Acetylase inhibitor SI-2 is a potent anti-inflammatory agent by inhibiting NLRP3 inflammasome activation
Acetylase inhibitor SI-2 is a potent anti-inflammatory agent by inhibiting NLRP3 inflammasome activation
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乙酰酶抑制剂 SI-2 通过抑制 NLRP3 炎症小体激活而成为有效的抗炎剂
DOI：
10.1016/j.intimp.2020.106829
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发表时间：
2020-10-01
影响因子：
5.6
通讯作者：
Zhao, Kai
中科院分区：
文献类型：
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作者：
Liu, Liping;Xu, Xueming;Zhao, Kai
Nod样受体家族pyrin domain-containing-3（NLRP 3）炎性体的异常激活与多种炎性疾病有关。靶向NLRP 3炎性体代表了治愈此类疾病的有希望的疗法。我们和其他人最近证明NLRP 3的乙酰化促进炎性小体活性，并且还表明赖氨酸乙酰转移酶抑制剂可能是一种有前途的治疗NLRP 3相关疾病的药物。在本研究中，通过寻找各种赖氨酸乙酰转移酶抑制剂，我们发现SI-2盐酸盐（SI-2 hydrochloride，SI-2），一种赖氨酸乙酰转移酶KAT 13 B（lysine acetyltransferases 13 B）的特异性抑制剂，在小鼠体内和离体人细胞中特异性阻断NLRP 3炎性小体激活。有趣的是，SI-2不影响NLRP 3的乙酰化。相反，它破坏了NLRP 3和含有CARD（ASC）的衔接子增殖相关斑点样蛋白之间的相互作用，然后阻断ASC斑点的形成。因此，我们的研究鉴定了NLRP 3炎性体的特异性抑制剂，并建议SI-2作为治疗NLRP 3驱动的疾病的潜在抑制剂。
Aberrant activation of Nod-like receptor family pyrin domain-containing-3 (NLRP3) inflammasome is implicated in a variety of inflammatory diseases. Targeting NLRP3 inflammasome represents a promising therapy to cure such diseases. We and others recently demonstrated that acetylation of NLRP3 promotes the inflammasome activity and also suggested lysine acetyltransferases inhibitors could be a kind of promising agents for treating NLRP3 associated disorders. In this study, by searching for kinds of lysine acetyltransferases inhibitors, we showed that SI-2 hydrochloride (SI-2), a specific inhibitor of lysine acetyltransferase KAT13B (lysine acetyltransferases 13B), specifically blocks NLRP3 inflammasome activation both in mice in vivo and in human cells ex vivo. Intriguingly, SI-2 does not affect the acetylation of NLRP3. Instead, it disrupts the interaction between NLRP3 and adaptor apoptosis-associated speck-like protein containing CARD (ASC), then blocks the formation of ASC speck. Thus, our study identified a specific inhibitor for NLRP3 inflammasome and suggested SI-2 as a potential inhibitory agent for the therapy of NLRP3-driven diseases.