Abstract
In Hedgehog (Hh) signaling, the GPCR-family protein Smoothened (Smo) acts as a signal transducer that is regulated by phosphorylation and ubiquitination, which ultimately change the cell surface accumulation of Smo. However, it is not clear whether Smo is regulated by other post-translational modifications, such as sumoylation. Here, we demonstrate that knockdown of the small ubiquitin-related modifier (SUMO) pathway components Ubc9 (a SUMO-conjugating enzyme E2), PIAS (a SUMO-protein ligase E3), and Smt3 (the SUMO isoform in Drosophila) by RNAi prevents Smo accumulation and alters Smo activity in the wing. We further show that Hh-induced-sumoylation stabilizes Smo, whereas desumoylation by Ulp1 destabilizes Smo in a phosphorylation independent manner. Mechanistically, we discover that excessive Krz, the Drosophila β-arrestin 2, inhibits Smo sumoylation and prevents Smo accumulation through Krz regulatory domain. Krz likely facilitates the interaction between Smo and Ulp1 because knockdown of Krz by RNAi attenuates Smo-Ulp1 interaction. Finally, we provide evidence that Cos2 is also sumoylated, which counteracts its inhibitory role on Smo accumulation in the wing. Taken together, we have uncovered a novel mechanism for Smo activation by sumoylation that is regulated by Hh and Smo interacting proteins.
Document Type
Article
Publication Date
2-14-2017
Digital Object Identifier (DOI)
https://doi.org/10.1038/srep42749
Funding Information
This study was supported by grant from the National Institutes of Health (GM079684). We thank the Shared Resource Facilities of the University of Kentucky Markey Cancer Center (supported by NCI grant P30 CA177558).
Repository Citation
Zhang, Jie; Liu, Yajuan; Jiang, Kai; and Jia, Jianhang, "SUMO Regulates the Activity of Smoothened and Costal-2 in Drosophila Hedgehog Signaling" (2017). Markey Cancer Center Faculty Publications. 95.
https://uknowledge.uky.edu/markey_facpub/95
Notes/Citation Information
Published in Scientific Reports, v. 7, article no. 42749, p. 1-14.
© The Author(s) 2017
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