RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control.
RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control.
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RTL8促进UBQLN 2的核定位到与蛋白质质量控制相关的亚核区室。
DOI：
10.1007/s00018-022-04170-z
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发表时间：
2022-03-05
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影响因子：
--
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中科院分区：
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脑表达泛蛋白（UBQLN）1、2和4是广泛参与蛋白质质量控制（PQC）途径（包括泛素蛋白酶体系统（UPS））的泛素衔接蛋白家族。一个家族成员UBQLN 2与包括ALS/FTD在内的许多神经退行性疾病有关。UBQLN 2通常存在于细胞质中，但在疾病中可易位至细胞核，如在亨廷顿病中，其促进突变亨廷顿蛋白的清除。然而，UBQLN 2如何易位到细胞核并清除异常的核蛋白还不清楚。在质谱筛选发现UBQLN 2相互作用，我们确定了一个家庭的小（13 kDa），高度同源的未表征的蛋白质，RTL 8，并确认UBQLN 2和RTL 8之间的相互作用，在体外使用重组蛋白和在体内使用小鼠脑组织。在内源性和过表达条件下，RTL 8定位于核仁。当与UBQLN 2共表达时，RTL 8促进UBQLN 2的核转位。RTL 8还在热休克期间促进UBQLN 2的核转位。UBQLN 2和RTL 8共定位于含有PQC组分的泛素富集的亚核结构内。RTL 8对UBQLN 2的核转位和亚核定位的强大作用不延伸到其他脑表达的泛素UBQLN 1和UBQLN 4。此外，与UBQLN 1和UBQLN 4相比，UBQLN 2优先稳定人细胞系和小鼠脑中的RTL 8水平，支持UBQLN之间的功能异质性。RTL 8作为一种新的UBQLN 2相互作用因子，可以将UBQLN 2募集到特定的核区室，在核蛋白质量控制中可能调节UBQLN 2的功能。
The brain expressed ubiquilins (UBQLNs) 1, 2 and 4 are a family of ubiquitin adaptor proteins that participate broadly in protein quality control (PQC) pathways, including the ubiquitin proteasome system (UPS). One family member, UBQLN2, has been implicated in numerous neurodegenerative diseases including ALS/FTD. UBQLN2 typically resides in the cytoplasm but in disease can translocate to the nucleus, as in Huntington’s disease where it promotes the clearance of mutant Huntingtin. How UBQLN2 translocates to the nucleus and clears aberrant nuclear proteins, however, is not well understood. In a mass spectrometry screen to discover UBQLN2 interactors, we identified a family of small (13 kDa), highly homologous uncharacterized proteins, RTL8, and confirmed the interaction between UBQLN2 and RTL8 both in vitro using recombinant proteins and in vivo using mouse brain tissue. Under endogenous and overexpressed conditions, RTL8 localizes to nucleoli. When co-expressed with UBQLN2, RTL8 promotes nuclear translocation of UBQLN2. RTL8 also facilitates UBQLN2’s nuclear translocation during heat shock. UBQLN2 and RTL8 colocalize within ubiquitin-enriched subnuclear structures containing PQC components. The robust effect of RTL8 on the nuclear translocation and subnuclear localization of UBQLN2 does not extend to the other brain-expressed ubiquilins, UBQLN1 and UBQLN4. Moreover, compared to UBQLN1 and UBQLN4, UBQLN2 preferentially stabilizes RTL8 levels in human cell lines and in mouse brain, supporting functional heterogeneity among UBQLNs. As a novel UBQLN2 interactor that recruits UBQLN2 to specific nuclear compartments, RTL8 may regulate UBQLN2 function in nuclear protein quality control.
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影响因子：
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作者：
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