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首页> 外文期刊>Molecular biology of the cell >Lysosomal Localization of Ubiquitinated Jun Requires Multiple Determinants in a Lysine-27-Linked Polyubiquitin Conjugate
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Lysosomal Localization of Ubiquitinated Jun Requires Multiple Determinants in a Lysine-27-Linked Polyubiquitin Conjugate

机译：泛素化Jun的溶酶体定位在赖氨酸27连接的多泛素结合物中需要多个决定簇。

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摘要

Ubiquitination regulates many cellular functions, including protein localization and degradation. Each function is specified by unique determinants in the conjugate. Ubiquitinated Jun is localized to lysosomes for degradation. Here, we characterized determinants of Jun ubiquitination and lysosomal localization by using ubiquitin-mediated fluorescence complementation (UbFC) in living cells and analysis of the stoichiometry of ubiquitin linked to Jun extracted from cells. The delta region of Jun and isoleucine-44 in ubiquitin were required for lysosomal localization of the conjugate. Ubiquitin containing only lysine-27, but no other single-lysine ubiquitin, mediated Jun ubiquitination, albeit at lower stoichiometry than wild-type ubiquitin. These conjugates were predominantly nuclear, but coexpression of lysine-27 and lysine-less ubiquitins enhanced the mean stoichiometry of Jun ubiquitination and lysosomal localization of the conjugate. Hepatocyte growth factor-regulated tyrosine kinase substrate (HRS) and tumor susceptibility gene 101 (TSG101) colocalized with ubiquitinated Jun. Knockdown of HRS or TSG101 inhibited lysosomal localization of ubiquitinated Jun and reduced Jun turnover. Ubiquitination of other Fos and Jun family proteins had distinct effects on their localization. Our results indicate that Jun is polyubiquitinated by E3 ligases that produce lysine- 27-linked chains. Lysosomal localization of the conjugate requires determinants in Jun and in ubiquitin that are recognized in part by TSG101 and HRS, facilitating selective translocation and degradation of ubiquitinated Jun.
机译：泛素化调节许多细胞功能，包括蛋白质定位和降解。每个功能由缀合物中的唯一决定簇指定。泛素化的Jun定位于溶酶体进行降解。在这里，我们通过在活细胞中使用泛素介导的荧光互补（UbFC）并分析与从细胞中提取的Jun相连的泛素的化学计量分析，来表征Jun泛素化和溶酶体定位的决定因素。缀合物的溶酶体定位需要泛素中的Jun和异亮氨酸-44的δ区。泛素仅包含赖氨酸27，但不包含其他单赖氨酸泛素介导的Jun泛素化，尽管化学计量比野生型泛素低。这些缀合物主要是核的，但是赖氨酸27和少赖氨酸的泛素的共表达增强了Jun泛素化和缀合物的溶酶体定位的平均化学计量。肝细胞生长因子调节的酪氨酸激酶底物（HRS）和肿瘤易感基因101（TSG101）与泛素化Jun共同定位。敲除HRS或TSG101抑制了泛素化Jun的溶酶体定位并降低Jun转换。其他Fos和Jun家族蛋白的泛素化对其定位具有明显的影响。我们的结果表明，Jun被产生赖氨酸27连接的链的E3连接酶多聚泛素化。缀合物的溶酶体定位需要Jun和遍在蛋白中的决定簇，TSG101和HRS部分识别这些决定簇，从而促进遍在蛋白化的Jun的选择性转运和降解。

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