SKP2 and OTUD1 govern non-proteolytic ubiquitination of YAP that promotes YAP nuclear localization and activity

Dysregulation of signaling pathways that control organ size, such as the AKT-mTOR and Hippo-YAP pathways, often leads to tumorigenesis and metastasis. The Hippo pathway effector YAP is a transcriptional coactivator overexpressed or activated in human tumors. Accumulating evidence has demonstrated that YAP promotes tumor initiation and/or progression in various types of cancer. YAP shuttles between the nucleus and the cytoplasm of the cell. When in the nucleus, YAP binds to transcription factors, such as SMAD, p73, RUNX, and the TEA domain (TEAD) family members, to activate gene transcription. The nuclear localization of YAP can be inhibited by the Hippo phosphorylation cascade and the cytoplasmic binding partners of YAP. In addition, YAP has previously been shown to be ubiquitinated by the SCFβ-TRCP complex and degraded by the proteasome. Recently, we discovered a novel mechanism by which non-proteolytic, K63-linked polyubiquitination of YAP promotes its nuclear localization, transcriptional activity, and growth-promoting function (Yao et al. Nat Commun 9:2269). Moreover, by screening ubiquitin E3 ligases implicated in K63- linked ubiquitination and a human deubiquitinase (DUB) library, we identified the SCFSKP2 complex and OTUD1, respectively, as the E3 ligase and the DUB that regulate this non-proteolytic ubiquitination without altering YAP protein level. Interestingly, this ubiquitination-mediated regulation of YAP is independent of Hippo pathway-mediated phosphorylation of YAP.