CDK5RAP3, a key defender of udder, modulates NLRP3 inflammasome activation by regulating autophagolysosome degradation in S. agalactiae-infected mastitis
CDK5RAP3, a key defender of udder, modulates NLRP3 inflammasome activation by regulating autophagolysosome degradation in S. agalactiae-infected mastitis
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DOI：
10.1016/j.ijbiomac.2023.123714
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发表时间：
2023-02-22
影响因子：
8.2
通讯作者：
Cai，Yafei
中科院分区：
文献类型：
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作者：
Yan，Hongchen;Zhou，Tianci;Cai，Yafei
无乳链球菌是临床和亚临床型乳房炎的主要病原菌之一，由于产奶量的急剧下降，影响动物福利，给养殖场造成巨大的经济损失。然而，两者都是OFS的真正致病机制。无乳酸菌引起的乳房炎以及控制炎症和自噬的调节剂在很大程度上是未知的。CDK5RAP3作为E3连接酶泛素样蛋白的底物，广泛参与多种信号通路的调节。我们的研究结果表明CDK5RAP3在感染的乳房炎中显著下调。无乳酸菌。令人惊讶的是，炎症小体的激活是由CDK5RAP3基因敲除触发的：上调NLRP3、IL1β和IL6，并切割Caspase1，由NF-κB启动，从而导致上睑下垂。此外，CDK5RAP3基因敲除后自噬标志物(Lc3B和P62)的积累表明，自噬溶酶体的降解途径被抑制，从而激活了NF-κB途径和NLRP3炎症小体。因此，我们的研究结果表明，下调或切除CDK5RAP3抑制自噬溶酶体的降解，通过激活NF-κB/NLRP3炎症小体而引起炎症，并触发细胞死亡。总之，CDK5RAP3是理解自噬和免疫反应之间相互作用的关键，它的抗炎作用将为临床治疗药物的发现提供新的线索。无乳乳腺炎。
Streptococcus agalactiae, as one of the main pathogens of clinical and subclinical mastitis, affects animal welfare and leads to huge economic losses to farms due to the sharp decline in milk yield. However, both the real pathogenic mechanisms ofS. agalactiae-induced mastitis and the regulator which controls the inflammation and autophagy are largely unknown. Served as a substrate of ubiquitin-like proteins of E3 ligase, CDK5RAP3 is widely involved in the regulation of multiple signaling pathways. Our findings revealed that CDK5RAP3 was significantly down-regulated in mastitis infected byS. agalactiae. Surprisingly, inflammasome activation was triggered by CDK5RAP3 knockdown: up-regulated NLRP3, IL1β and IL6, and cleaved caspase1 promoting by NF-κB, thereby resulting in pyroptosis. Additionally, the accumulation of autophagy markers (LC3B and p62) after CDK5RAP3 knockdown suggested that the autophagolysosome degradation pathway was inhibited, thereby activating the NF-κB pathway and NLRP3 inflammasome. Hence, our findings suggest that downregulation or ablation of CDK5RAP3 inhibits autophagolysosome degradation, causes inflammation by activating the NF-κB /NLRP3 inflammasome, and triggers cell death. In conclusion, CDK5RAP3 holds the key to understanding the interaction between autophagy and immune responses, its anti-inflammatory role in this study will throw new light on the clinical drug discovery to cureS. agalactiaemastitis.