蛋白质酸酶PP6促进了RIPK1依赖的PANoptosis
Ratnakar R Bynigeri1, R K Subbarao Malireddi1, Raghvendra Mall1,2
1Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
BMC biology
|May 28, 2024
概括
蛋白酸酶6 (PP6) 调节转化生长因子β-激活激酶1抑制剂诱导的PANoptosis. 损失PP6通过影响RIPK1酸化来减少细胞死亡,为炎症性疾病提供治疗点.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 分子医学是分子医学.
背景情况:
- 天生的免疫系统对病原体进行防御,转化生长因子β激活激酶1 (TAK1) 作为关键调节剂.
- 病原体抑制TAK1,促使宿主通过PANoptosis进行防御,这是由RIPK1-PANoptosome介导的溶性细胞死亡途径.
- 失调的PANoptosis有助于炎症病理,需要对其调节机制进行研究.
研究的目的:
- 为了确定TAK1抑制剂 (TAK1i) 诱导的PANoptosis的分子调节剂.
- 阐明RIPK1酸化在TAK1i诱导的细胞死亡中的作用.
- 探索与PANoptosis相关的炎症状况的潜在治疗点.
主要方法:
- 利用基于细胞死亡的CRISPR屏幕来识别TAK1i诱导的PANoptosis的调节者.
- 分析了蛋白质酸酶6 (PP6) 成分耗尽对PANoptosis的影响.
- 研究了PP6在特定部位 (S166和S321) 上对RIPK1酸化的影响.
主要成果:
- 确定了PP6全酶成分作为TAK1i诱导的PANoptosis的关键调节剂.
- 催化子单元PPPP6C的丧失显著损害了TAK1i诱导的PANoptosis.
- 联合消耗PP6调节子单元 (PPP6R1,PPP6R2,PPP6R3) 阻断了TAK1i诱导的细胞死亡.
- PP6在S166 (亲死亡) 促进了RIPK1自身酸化,并在S321 (亲生存) 减少了酸化.
结论:
- 酸酶PP6复合体对于激活TAK1i诱导的,依赖RIPK1的PANoptosis至关重要.
- PP6调节RIPK1酸化,影响细胞命运,以应对TAK1抑制.
- PP6复合体代表了管理炎症疾病的潜在治疗标.
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