Lei Hu, Yang Li, Wang Yingying, Zou Zhihui, Liu Meng, Xu Hanzhang, Wu Yingli
Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
Research Units of Stress and Tumor (2019RU043), Chinese Academy of Medical Sciences, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
Exp Hematol Oncol. 2022 Jul 14;11(1):42. doi: 10.1186/s40164-022-00295-w.
Pyruvate kinase M2 (PKM2) plays an important role in the metabolism and proliferation of leukemia cells. Here, we show that deubiquitinase JOSD2, a novel tumor suppressor, blocks PKM2 nuclear localization by reducing its K433 acetylation in acute myeloid leukemia (AML). Firstly, we show that JOSD2 is significantly down-regulated in primary AML cells. Reconstitute of JOSD2 in AML cells significantly inhibit cell viability and induce cell apoptosis. Next, PKM2 is identified as a novel interaction protein of JOSD2 by mass spectrometry, co- immunoprecipitation and co-immunofluorescence in HL60 cells. However, JOSD2 does not affect PKM2 protein stability. We then found out that JOSD2 inhibits nuclear localization of PKM2 by reducing its K433 acetylation modification, accompanied by decreased downstream gene expression through non-glycolytic functions. Finally, JOSD2 decreases AML progression in vivo. Taken together, we propose that JOSD2 blocks PKM2 nuclear localization and reduces AML progression.
丙酮酸激酶M2（PKM2）在白血病细胞的代谢和增殖中起重要作用。在此，我们表明去泛素化酶JOSD2是一种新型肿瘤抑制因子，它通过降低急性髓系白血病（AML）中PKM2的K433乙酰化水平来阻断PKM2的核定位。首先，我们发现JOSD2在原发性AML细胞中显著下调。在AML细胞中重建JOSD2可显著抑制细胞活力并诱导细胞凋亡。接下来，通过质谱、共免疫沉淀和HL60细胞中的共免疫荧光鉴定出PKM2是JOSD2的一种新型相互作用蛋白。然而，JOSD2不影响PKM2蛋白的稳定性。然后我们发现JOSD2通过降低PKM2的K433乙酰化修饰来抑制PKM2的核定位，同时伴随着通过非糖酵解功能导致下游基因表达降低。最后，JOSD2在体内可减少AML进展。综上所述，我们提出JOSD2可阻断PKM2的核定位并减少AML进展。
