Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer
Dysregulation of INF2-mediated mitochondrial fission in SPOP-mutated prostate cancer
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SPOP 突变前列腺癌中 INF2 介导的线粒体分裂失调
DOI：
10.1371/journal.pgen.1006748
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发表时间：
2017-04-01
期刊：
影响因子：
4.5
通讯作者：
Wang, Chenji
中科院分区：
文献类型：
--
作者：
Jin, Xiaofeng;Wang, Jie;Wang, Chenji
前列腺癌外显子组和基因组的下一代测序已经确定了许多遗传变异。SPOP（Speckle-type POZ Protein）是原发性前列腺癌中最常发生突变的基因之一，表明SPOP是前列腺癌发生和进展的潜在驱动因素。然而，SPOP突变如何促进前列腺癌的发病机制仍然知之甚少。SPOP作为CUL 3-RBX 1 E3泛素连接酶复合物的衔接蛋白，其通常募集底物用于泛素化和随后的降解。内质网定位亚型的ERP 2蛋白反向转录因子2（INF 2）介导肌动蛋白聚合在内质网-线粒体交叉点，并促进DRP 1招聘到线粒体，这是一个关键步骤，在线粒体分裂。在这里，我们发现SPOP识别INF 2的C-末端区域中富含Ser/Thr（S/T）的基序，并触发INF 2的非典型聚泛素化。这些泛素化修饰不会导致INF 2的不稳定性，而是减少了INF 2在ER中的定位和与尿道相关的DRP 1斑点的形成，因此消除了其促进线粒体分裂的能力。INF 2突变体逃避SPOP介导的泛素化更有效地促进线粒体分裂。此外，前列腺癌相关的SPOP突变体增加了ER中INF 2的定位并促进线粒体分裂，可能是通过显性负效应来抑制内源性SPOP。此外，INF 2对于SPOP失活诱导的前列腺癌细胞迁移和侵袭是重要的。这些发现揭示了INF 2功能和定位调节的新分子事件，并为了解SPOP突变与前列腺癌线粒体动力学失调之间的关系提供了见解。
Next-generation sequencing of the exome and genome of prostate cancers has identified numerous genetic alternations. SPOP (Speckle-type POZ Protein) was one of the most frequently mutated genes in primary prostate cancer, suggesting SPOP is a potential driver of prostate cancer development and progression. However, how SPOP mutations contribute to prostate cancer pathogenesis remains poorly understood. SPOP acts as an adaptor protein of the CUL3-RBX1 E3 ubiquitin ligase complex that generally recruits substrates for ubiquitination and subsequent degradation. ER-localized isoform of the formin protein inverted formin 2 (INF2) mediates actin polymerization at ER-mitochondria intersections and facilitates DRP1 recruitment to mitochondria, which is a critical step in mitochondrial fission. Here, we revealed that SPOP recognizes a Ser/Thr (S/T)-rich motif in the C-terminal region of INF2 and triggers atypical polyubiquitination of INF2. These ubiquitination modifications do not lead to INF2 instability, but rather reduces INF2 localization in ER and mitochondrially associated DRP1 puncta formation, therefore abrogates its ability to facilitate mitochondrial fission. INF2 mutant escaping from SPOP-mediated ubiquitination is more potent in prompting mitochondrial fission. Moreover, prostate cancer-associated SPOP mutants increase INF2 localization in ER and promote mitochondrial fission, probably through a dominant-negative effect to inhibit endogenous SPOP. Moreover, INF2 is important for SPOP inactivation-induced prostate cancer cell migration and invasion. These findings reveal novel molecular events underlying the regulation of INF2 function and localization, and provided insights in understanding the relationship between SPOP mutations and dysregulation of mitochondrial dynamics in prostate cancer.