Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis
Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis
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DOI：
10.1038/nm.3740
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发表时间：
2014-12-01
期刊：
影响因子：
82.9
通讯作者：
Bassermann, Florian
中科院分区：
文献类型：
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作者：
Baumann, Ursula;Fernandez-Saiz, Vanesa;Bassermann, Florian
我们在人类B细胞淋巴瘤中寻找影响泛素-蛋白酶体系统的遗传改变。该方法在套细胞淋巴瘤（MCL）中频繁缺失的最小共同区域内鉴定了FBXO 25。FBXO 25编码BX孤儿F-box蛋白，其决定SCF（SKP 1-CUL 1-F-box）（FBXO 25）泛素连接酶复合物的底物特异性。无偏筛选发现促生存蛋白HCLS 1相关蛋白X-1（HAX-1）作为FBXO 25的真正底物，FBXO 25在凋亡应激后被靶向。蛋白激酶C δ（PRKCD）通过磷酸化FBXO 25和HAX-1启动这一过程，从而将核FBXO 25空间定向到线粒体！HAX-1我们在原发性人MCL中的分析鉴定了FBXO 25的单等位基因缺失和稳定的HAX 1磷酸降解决定子突变。因此，FBXO 25缺失的MCL细胞中FBXO 25的重新表达促进细胞死亡，而HAX-1磷酸降解决定子突变体的表达抑制细胞凋亡。此外，FBXO 25的敲低显著加速了E mu-Myc小鼠和人MCL异种移植模型中淋巴瘤的发展。我们一起确定了一个PRKCD依赖的促凋亡机制控制HAX-1的稳定性，我们提出FBXO 25作为一个单倍不足的肿瘤抑制因子和HAX 1是一个原癌基因MCL。
We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an BX orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box)(FBXO25) ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase C delta (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondria! HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in E mu-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.