NEDD4L limits cAMP signaling through ubiquitination of CREB‐regulated transcription coactivator 3

The transcription factor cAMP‐responsive element‐binding protein (CREB) is involved in a variety of physiologic processes. Although its activity appears to be largely correlated with its phosphorylation status, cAMP‐mediated dephosphorylation and the subsequent nuclear migration of the CREB‐regulated transcription factors (CRTCs) are required to stimulate CREB transcriptional activity. Among the 3 identified mammalian homologs of CRTCs, CRTC3 has been shown to be expressed predominantly in adipose tissues in response to catecholamine signals that regulate lipid metabolism. Here, we show that prolonged cAMP signaling down‐regulates CRTC3 in a proteasome‐dependent manner and that neural precursor cell‐expressed developmentally down‐regulated gene 4‐like (NEDD4L), a specific ubiquitin ligase for CRTC3, is responsible for this process. By recognizing the PY motif of CRTC3, NEDD4L interacts with CRTC3 and promotes its polyubiquitination. Interaction between NEDD4L and CRTC3 is further boosted by cAMP signaling, and this enhanced interaction appears to be dependent on the cAMP‐mediated phosphorylation of NEDD4L at the Ser448 site. Furthermore, we show that food withdrawal stimulates NEDD4L phosphorylation in mice, which then show a decrease of adipose tissue CRTC3 protein levels. Together, these results suggest that NEDD4L plays a key role in the feedback regulation of cAMP signaling by limiting CRTC3 protein levels.—Kim, Y.‐H., Yoo, H., Hong, A.‐R., Kwon, M., Kang, S.‐W., Kim, K., Song, Y. NEDD4L limits cAMP signaling through ubiquitination of CREB‐regulated transcription coactivator 3. FASEB J. 32, 4053–4062 (2018). www.fasebj.org