小柯机器人

美国哈佛医学院Xu Wu研究组的一项最新工作发现，脂肪酸和ZDHHC19的扩增通过S -棕榈酰化促进信号传导与转录激活因子3（STAT3）的活化。该项研究成果2019年8月28日在线发表于《自然》。

研究人员发现STAT3在SH2（SRC homology 2）结构域存在翻译后的S-棕榈酰化，其促进STAT3的二聚化和转录激活。脂肪酸可以通过增强其棕榈酰化作用与细胞因子刺激协同作用直接激活STAT3。研究人员进一步鉴定ZDHHC19为调节STAT3的棕榈酰酰基转移酶。细胞因子刺激通过促进ZDHHC19和STAT3之间的结合来增加STAT3棕榈酰化，这由GRB2的SH3结构域介导。沉默ZDHHC19能够阻断STAT3棕榈酰化和二聚化，并损害细胞因子和脂肪酸诱导的STAT3活化。ZDHHC19经常在多种人类癌症中扩增，包括39％的肺鳞状细胞癌。高水平的ZDHHC19与患者样品中高水平的核内STAT3相关。此外，ZDHHC19在肺鳞状细胞癌细胞中的敲除显著阻断STAT3活性，并且抑制由脂肪酸诱导的肿瘤球形成以及在小鼠体内模型中由高脂肪饮食诱导的肿瘤发生。

这些研究表明，脂肪酸和ZDHHC19介导的棕榈酰化是调节STAT3的信号，这为棕榈酰化失调与炎症和癌症之间的联系提供了证据。

据悉， STAT3在调节细胞命运、炎症和免疫方面具有重要作用。细胞因子和生长因子通过激酶介导的酪氨酸磷酸化和二聚化激活STAT3。目前尚不清楚其他因素是否通过不同的机制促进STAT3的激活。

附：英文原文

Title: Fatty acids and cancer-amplified ZDHHC19 promote STAT3 activation through S -palmitoylation

Author: Jixiao Niu, Yang Sun, Baoen Chen, Baohui Zheng, Gopala K. Jarugumilli, Sarah R. Walker, Aaron N. Hata, Mari Mino-Kenudson, David A. Frank, Xu Wu

Issue&Volume: 2019-08-28

Abstract: Signal transducer and activator of transcription 3 (STAT3) has a critical role in regulating cell fate, inflammation and immunity1,2. Cytokines and growth factors activate STAT3 through kinase-mediated tyrosine phosphorylation and dimerization3,4. It remains unknown whether other factors promote STAT3 activation through different mechanisms. Here we show that STAT3 is post-translationally S-palmitoylated at the SRC homology 2 (SH2) domain, which promotes the dimerization and transcriptional activation of STAT3. Fatty acids can directly activate STAT3 by enhancing its palmitoylation, in synergy with cytokine stimulation. We further identified ZDHHC19 as a palmitoyl acyltransferase that regulates STAT3. Cytokine stimulation increases STAT3 palmitoylation by promoting the association between ZDHHC19 and STAT3, which is mediated by the SH3 domain of GRB2. Silencing ZDHHC19 blocks STAT3 palmitoylation and dimerization, and impairs the cytokine- and fatty-acid-induced activation of STAT3. ZDHHC19 is frequently amplified in multiple human cancers, including in 39% of lung squamous cell carcinomas. High levels of ZDHHC19 correlate with high levels of nuclear STAT3 in patient samples. In addition, knockout of ZDHHC19 in lung squamous cell carcinoma cells significantly blocks STAT3 activity, and inhibits the fatty-acid-induced formation of tumour spheres as well as tumorigenesis induced by high-fat diets in an in vivo mouse model. Our studies reveal that fatty-acid- and ZDHHC19-mediated palmitoylation are signals that regulate STAT3, which provides evidence linking the deregulation of palmitoylation to inflammation and cancer.

DOI: 10.1038/s41586-019-1511-x

Source: https://www.nature.com/articles/s41586-019-1511-x

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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