Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA92093.
Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, CA92093.
Mol Biol Cell. 2023 Aug 1;34(9):ar93. doi: 10.1091/mbc.E23-02-0055. Epub 2023 May 24.
The α-arrestin ARRDC3 is a recently discovered tumor suppressor in invasive breast cancer that functions as a multifaceted adaptor protein to control protein trafficking and cellular signaling. However, the molecular mechanisms that control ARRDC3 function are unknown. Other arrestins are known to be regulated by posttranslational modifications, suggesting that ARRDC3 may be subject to similar regulatory mechanisms. Here we report that ubiquitination is a key regulator of ARRDC3 function and is mediated primarily by two proline-rich PPXY motifs in the ARRDC3 C-tail domain. Ubiquitination and the PPXY motifs are essential for ARRDC3 function in regulating GPCR trafficking and signaling. Additionally, ubiquitination and the PPXY motifs mediate ARRDC3 protein degradation, dictate ARRDC3 subcellular localization, and are required for interaction with the NEDD4-family E3 ubiquitin ligase WWP2. These studies demonstrate a role for ubiquitination in regulating ARRDC3 function and reveal a mechanism by which ARRDC3 divergent functions are controlled.
α-arrestin ARRDC3 是一种新发现的浸润性乳腺癌肿瘤抑制因子，作为一种多功能衔接蛋白，可控制蛋白转运和细胞信号转导。然而，控制 ARRDC3 功能的分子机制尚不清楚。其他 arrestin 已知受翻译后修饰的调控，这表明 ARRDC3 可能受到类似的调控机制的调控。在这里，我们报告泛素化是 ARRDC3 功能的关键调节剂，主要由 ARRDC3 C 尾结构域中的两个富含脯氨酸的 PPXY 基序介导。泛素化和 PPXY 基序对于 ARRDC3 在调节 GPCR 转运和信号转导中的功能至关重要。此外，泛素化和 PPXY 基序介导 ARRDC3 蛋白降解，决定 ARRDC3 亚细胞定位，并与 NEDD4 家族 E3 泛素连接酶 WWP2 相互作用。这些研究表明泛素化在调节 ARRDC3 功能中的作用，并揭示了控制 ARRDC3 不同功能的机制。
