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The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network

机译：PTEN的去泛素化和定位受HAUSP-PML网络调控

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Nuclear exclusion of the PTEN (phosphatase and tensin homo-logue deleted in chromosome 10) tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitiny-lation of PTEN at specific lysine residues regulates its nuclear-cytoplasmic partitioning. Here we show that functional pro-myelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML-RARα fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARα degradation, such as all- trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML-DAXX-HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization.
机译：PTEN（在10号染色体中删除的磷酸酶和张力蛋白同源物）肿瘤抑制子的核排斥与癌症进展有关。但是，目前尚不清楚导致人类癌症中这种异常PTEN定位的机制。我们以前曾报道过，PTEN在特定赖氨酸残基上的泛素化调节了其核质分配。在这里，我们展示了功能性促幼粒细胞白血病蛋白（PML）核体通过对抗先前未知的PTEN去泛素化酶，疱疹病毒相关的泛素特异性蛋白酶（HAUSP，也称为USP7）的作用来协调PTEN定位。 PTEN才能进入细胞核需要此分子框架的完整性。我们发现PTEN异常定位于急性早幼粒细胞白血病，其中PML功能被PML-RARα融合癌蛋白破坏。值得注意的是，使用引发PML-RARα降解的药物（例如全反式维甲酸或三氧化二砷）进行治疗，可以恢复PTEN核。我们证明，PML通过涉及衔接蛋白DAXX（死亡域相关蛋白）的机制反对HAUSP对PTEN的活性。支持这种范例，我们表明HAUSP在人类前列腺癌中过表达，并且与PTEN核排斥有关。因此，我们的研究结果描绘了一个先前未知的控制PTEN去泛素化和运输的PML-DAXX-HAUSP分子网络，该网络受人类癌症中的致癌线索干扰，从而为PTEN亚细胞区室化定义了新的去泛素化依赖性模型。

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