Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 77030, USA.
Nat Commun. 2018 Jun 11;9(1):2269. doi: 10.1038/s41467-018-04620-y.
Dysregulation of YAP localization and activity is associated with pathological conditions such as cancer. Although activation of the Hippo phosphorylation cascade is known to cause cytoplasmic retention and inactivation of YAP, emerging evidence suggests that YAP can be regulated in a Hippo-independent manner. Here, we report that YAP is subject to non-proteolytic, K63-linked polyubiquitination by the SCF E3 ligase complex (SKP2), which is reversed by the deubiquitinase OTUD1. The non-proteolytic ubiquitination of YAP enhances its interaction with its nuclear binding partner TEAD, thereby inducing YAP's nuclear localization, transcriptional activity, and growth-promoting function. Independently of Hippo signaling, mutation of YAP's K63-linkage specific ubiquitination sites K321 and K497, depletion of SKP2, or overexpression of OTUD1 retains YAP in the cytoplasm and inhibits its activity. Conversely, overexpression of SKP2 or loss of OTUD1 leads to nuclear localization and activation of YAP. Altogether, our study sheds light on the ubiquitination-mediated, Hippo-independent regulation of YAP.
YAP 定位和活性的失调与癌症等病理状况有关。尽管已知 Hippo 磷酸化级联的激活会导致 YAP 的细胞质保留和失活，但新出现的证据表明，YAP 可以以非 Hippo 依赖的方式进行调节。在这里，我们报告 YAP 可被 SCF E3 连接酶复合物（SKP2）进行非蛋白水解的、K63 连接的多泛素化，该过程可被去泛素酶 OTUD1 逆转。YAP 的非蛋白水解泛素化增强了其与核结合伴侣 TEAD 的相互作用，从而诱导 YAP 的核定位、转录活性和促进生长的功能。独立于 Hippo 信号，YAP 的 K63 连接特异性泛素化位点 K321 和 K497 的突变、SKP2 的耗竭或 OTUD1 的过表达将 YAP 保留在细胞质中并抑制其活性。相反，SKP2 的过表达或 OTUD1 的缺失导致 YAP 的核定位和激活。总的来说，我们的研究揭示了 YAP 的泛素化介导的、非 Hippo 依赖的调节。
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