Key Laboratory of Gene Engineering of the Ministry of Education, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
Department of Neurosurgery, The First People's Hospital of Changzhou, Changzhou, Jiangsu 213000, China; Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213000, China.
Cell Rep. 2018 Apr 17;23(3):838-851. doi: 10.1016/j.celrep.2018.03.096.
p38 signaling is broadly involved in controlling inflammation and stress-induced cell death; however, the mechanisms controlling its activity have seldom been studied. Here, we report that TRIM9 short isoform (TRIM9s) potentiates p38 signaling by stabilizing MKK6. Mechanistic studies revealed that TRIM9s promotes the K63-linked ubiquitination of MKK6 at Lys82, thus inhibiting the degradative K48-linked ubiquitination of MKK6 at the same lysine. MKK6 could also stabilize TRIM9s by promoting the phosphorylation of TRIM9s at Ser76/80 via p38, thereby blocking the ubiquitin-proteasome pathway. Further functional analyses showed that p38 signaling plays a critical role in suppressing glioblastoma progression. Co-reduction of MKK6 and TRIM9s is significantly associated with overall poor survival of glioblastoma patients. We identify a positive feedback loop in p38 signaling generated by MKK6-TRIM9s, which suppresses glioblastoma progression, and we provide insights into the mechanisms by which TRIM9s and MKK6 potentiate p38 signaling through mutual stabilization.
p38 信号广泛参与调控炎症和应激诱导的细胞死亡；然而，其活性的调控机制鲜少被研究。在此，我们报告 TRIM9 短亚型（TRIM9s）通过稳定 MKK6 来增强 p38 信号。机制研究显示，TRIM9s 在赖氨酸 82 处促进 MKK6 的 K63 连接泛素化，从而抑制同一赖氨酸的 K48 连接泛素化降解。MKK6 还可以通过 p38 促进 TRIM9s 在丝氨酸 76/80 处的磷酸化，从而阻断泛素蛋白酶体途径，从而稳定 TRIM9s。进一步的功能分析表明，p38 信号在抑制胶质母细胞瘤进展中起关键作用。MKK6 和 TRIM9s 的共下调与胶质母细胞瘤患者的总体不良预后显著相关。我们鉴定出 MKK6-TRIM9s 产生的 p38 信号的正反馈回路，其抑制胶质母细胞瘤进展，我们深入了解了 TRIM9s 和 MKK6 通过相互稳定增强 p38 信号的机制。
