SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer
SPOP mutations promote p62/SQSTM1-dependent autophagy and Nrf2 activation in prostate cancer
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SPOP 突变促进前列腺癌中 p62/SQSTM1 依赖性自噬和 Nrf2 激活
DOI：
10.1038/s41418-021-00913-w
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发表时间：
2022-01-06
影响因子：
12.4
通讯作者：
Wang, Chenji
中科院分区：
文献类型：
--
作者：
Shi, Qing;Jin, Xiaofeng;Wang, Chenji
p62/SQSTM 1是一种选择性自噬受体，其驱动泛素化货物朝向自噬降解。这种受体也是一种应激诱导的支架蛋白，通过激活Nrf 2途径帮助细胞科普氧化应激。p62的功能障碍与多种神经退行性疾病和癌症密切相关。编码E3泛素连接酶底物结合衔接子SPOP的基因在前列腺癌（PCa）中经常发生突变，但SPOP突变如何促进PCa肿瘤发生的分子机制仍知之甚少。在这里，我们报告，胞质SPOP结合并诱导非降解泛素化p62在残基K420内的乌巴域。这种蛋白质修饰降低了p62斑点形成、液相凝聚、二聚化和泛素结合能力，从而抑制了p62依赖性自噬。此外，我们表明，SPOP缓解p62介导的Keap 1隔离，最终降低Nrf 2介导的抗氧化基因的转录激活。我们进一步表明，PCa相关的SPOP突变体失去了泛素化p62的能力，而是以显性负性方式促进自噬和氧化还原反应。因此，我们的研究结果表明自噬和Nrf 2激活在SPOP突变的PCa的肿瘤发生中的致癌作用。
p62/SQSTM1 is a selective autophagy receptor that drives ubiquitinated cargos towards autophagic degradation. This receptor is also a stress-induced scaffold protein that helps cells to cope with oxidative stress through activation of the Nrf2 pathway. Functional disorders of p62 are closely associated with multiple neurodegenerative diseases and cancers. The gene encoding the E3 ubiquitin ligase substrate-binding adapterSPOPis frequently mutated in prostate cancer (PCa), but the molecular mechanisms underlying how SPOP mutations contribute to PCa tumorigenesis remain poorly understood. Here, we report that cytoplasmic SPOP binds and induces the non-degradative ubiquitination of p62 at residue K420 within the UBA domain. This protein modification decreases p62 puncta formation, liquid phase condensation, dimerization, and ubiquitin-binding capacity, thereby suppressing p62-dependent autophagy. Moreover, we show that SPOP relieves p62-mediated Keap1 sequestration, which ultimately decreases Nrf2-mediated transcriptional activation of antioxidant genes. We further show that PCa-associated SPOP mutants lose the capacity to ubiquitinate p62 and instead promote autophagy and the redox response in a dominant-negative manner. Thus, our findings indicate oncogenic roles of autophagy and Nrf2 activation in the tumorigenesis of SPOP-mutated PCa.