Kim Jaehyun, Tsuruta Fuminori, Okajima Tomomi, Yano Sarasa, Sato Ban, Chiba Tomoki
Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; PhD Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan; Life Science Center of Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):220-226. doi: 10.1016/j.bbrc.2017.10.049. Epub 2017 Oct 12.
Kelch-like protein 7 (KLHL7) is a component of Cul3-based Cullin-RING ubiquitin ligase. Recent studies have revealed that mutations in klhl7 gene cause several disorders, such as retinitis pigmentosa (RP). Although KLHL7 is considered to be crucial for regulating the protein homeostasis, little is known about its biological functions. In this study, we report that KLHL7 increases terminal uridylyl transferase 1 (TUT1) ubiquitination involved in nucleolar integrity. TUT1 is normally localized in nucleolus; however, expression of KLHL7 facilitates a vulnerability of nucleolar integrity, followed by a decrease of TUT1 localization in nucleolus. On the other hand, pathogenic KLHL7 mutants, which causes an onset of RP, have little effect on both nucleolar integrity and TUT1 localization. Finally, KLHL7 increases TUT1 ubiquitination levels. Taken together, these results imply that KLHL7 is a novel regulator of nucleolus associated with TUT1 ubiquitination. Our study may provide a valuable information to elucidate a pathogenic mechanism of RP.
类 Kelch 蛋白 7（KLHL7）是基于 Cul3 的 Cullin-RING 泛素连接酶的一个组成部分。最近的研究表明，klhl7 基因的突变会导致多种疾病，如视网膜色素变性（RP）。尽管 KLHL7 被认为对调节蛋白质稳态至关重要，但其生物学功能却知之甚少。在本研究中，我们报告 KLHL7 增加了参与核仁完整性的末端尿苷酰转移酶 1（TUT1）的泛素化。TUT1 通常定位于核仁；然而，KLHL7 的表达会导致核仁完整性受损，随后 TUT1 在核仁中的定位减少。另一方面，导致 RP 发病的致病性 KLHL7 突变体对核仁完整性和 TUT1 定位均无影响。最后，KLHL7 增加了 TUT1 的泛素化水平。综上所述，这些结果表明 KLHL7 是一种与 TUT1 泛素化相关的新型核仁调节因子。我们的研究可能为阐明 RP 的致病机制提供有价值的信息。
