Palmitoylation restricts SQSTM1/p62-mediated autophagic degradation of NOD2 to modulate inflammation
Palmitoylation restricts SQSTM1/p62-mediated autophagic degradation of NOD2 to modulate inflammation
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棕榈酰化限制 SQSTM1/p62 介导的 NOD2 自噬降解以调节炎症
DOI：
10.1038/s41418-022-00942-z
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发表时间：
2022-01
影响因子：
12.4
通讯作者：
Cui Jun
中科院分区：
文献类型：
--
作者：
Zhou Lingli;He Xing;Wang Liqiu;Wei Ping;Cai Zhe;Zhang Song;Jin Shouheng;Zeng Huasong;Cui Jun
核苷酸结合的寡聚化结构域蛋白2(NOD2)能感应细菌的肽聚糖，从而诱导促炎和抗菌反应。NOD2信号的失调参与了多种炎症性疾病的发生。最近，S-棕榈酰化作为一种新型的翻译后修饰，被报道在NOD2的膜结合和配体诱导的信号转导中起着关键作用，但它对NOD2稳定性的影响尚不清楚。在这里，我们发现抑制S棕榈酰化促进了SQSTM1/P62介导的NOD2的自噬降解，而S棕榈酰化促进了NOD2的稳定性。此外，我们在自身炎症性疾病中发现了NOD2短亚型的一个功能获得型R444C变异体(NOD2S-R444C)，它通过其高水平的S棕榈酰化而引起过度炎症。在机制上，NOD2S-R444C突变体与ZDHHC5具有较强的结合能力，促进其S棕榈酰化，并通过减少与SQSTM1/P62的相互作用来抑制其自噬降解。综上所述，我们的研究揭示了S棕榈酰化通过与自噬的串扰来控制NOD2稳定性的调节作用，并为研究功能失调的S棕榈酰化与炎症性疾病的发生之间的关系提供了见解。
The nucleotide-binding oligomerization domain protein 2 (NOD2) senses bacterial peptidoglycan to induce proinflammatory and antimicrobial responses. Dysregulation of NOD2 signaling is involved in multiple inflammatory disorders. Recently, S-palmitoylation, a novel type of post-translational modification, is reported to play a crucial role in membrane association and ligand-induced signaling of NOD2, yet its influence on the stability of NOD2 is unclear. Here we show that inhibition of S-palmitoylation facilitates the SQSTM1/p62-mediated autophagic degradation of NOD2, while S-palmitoylation of NOD2 by ZDHHC5 promotes the stability of NOD2. Furthermore, we identify a gain-of-function R444C variant of NOD2 short isoform (NOD2s-R444C) in autoinflammatory disease, which induces excessive inflammation through its high S-palmitoylation level. Mechanistically, the NOD2s-R444C variant possesses a stronger binding ability to ZDHHC5, which promotes its S-palmitoylation, and restricts its autophagic degradation by reducing its interaction with SQSTM1/p62. Taken together, our study reveals the regulatory role of S-palmitoylation in controlling NOD2 stability through the crosstalk with autophagy, and provides insights into the association between dysfunctional S-palmitoylation and the occurrence of inflammatory diseases.
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