MassIVE MSV000084683

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Identification of the NEDDylated proteome by Nedd8-specific K-GG mass spectrometry uncovers modulation of Actin dynamics by neddylated Cofilin

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Description

Neddylation is the post-translational protein modification that is most closely related to ubiquitination. The Ubiquitin-like protein NEDD8 is mostly studied for its role in activating the Cullin-RING E3 Ubiquitin ligases, however little is known about other NEDD8 targets. We developed serial NEDD8-Ubiquitin Substrate Profiling (sNUSP), a method that employs Nedd8-R74K knock-in cells allowing discrimination of endogenous NEDD8- and Ubiquitin-modification sites by mass spectrometry after Lys-C digestion and K-GG- peptide enrichment. Using sNUSP, we identified 607 neddylation sites dynamically regulated by the neddylation inhibitor MLN4924 and the de-neddylating enzyme NEDP1/SENP8. Among the candidates, we characterized lysine 112 (K112) of the Actin regulator Cofilin as a novel neddylation event. Global inhibition of neddylation in developing neurons leads to cytoskeletal defects, altered Actin dynamics and neurite growth impairments and site-specific neddylation of Cofilin at K112 regulates neurite outgrowth. These data show that Cofilin neddylation contributes to the regulation of neuronal Actin dynamics. [doi:10.25345/C5WD5M] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: neddylation ; nedd8 ; senp8 ; cofilin ; ubiquitin ; MLN4924 ; nedp1

Contact

Principal Investigators:
(in alphabetical order) 		Donald Kirkpatrick, Genentech, United States
erik verschueren, Genentech, United States
Submitting User: erikv
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