Funding Source

NCI National Institutes of Health, American Cancer Society Research Scholars

Grant Number

5 T32 CA121949, RSG-11-224-01-DMC

Department

Department of Chemistry

Document Type

Article

Publication Date

5-24-2013

Abstract

The bacterial effector protein cycle inhibiting factor (CIF) converts glutamine 40 of NEDD8 to glutamate (Q40E), causing cytopathic effects and inhibiting cell proliferation. Although these have been attributed to blocking the functions of cullin-RING ubiquitin ligases, how CIF modulates NEDD8-dependent signaling is unclear. Here we use conditional NEDD8-dependent yeast to explore the effects of CIF on cullin neddylation. Although CIF causes cullin deneddylation and the generation of free NEDD8 Q40E, inhibiting the COP9 signalosome (CSN) allows Q40E to form only on NEDD8 attached to cullins. In the presence of the CSN, NEDD8 Q40E is removed from cullins more rapidly than NEDD8, leading to a decrease in steady-state cullin neddylation. As NEDD8 Q40E is competent for cullin conjugation in the absence of functional CSN and with overexpression of the NEDD8 ligase Dcn1, our data are consistent with NEDD8 deamidation causing enhanced deneddylation of cullins by the CSN. This leads to a dramatic change in the extent of activated cullin-RING ubiquitin ligases.

Comments

DOI: 10.1074/jbc.M112.448258

PubMed ID: 23589306

Footnotes

This work was supported, in whole or in part, by NCI National Institutes of Health Training Grant 5 T32 CA121949 (to T. B. T.). This work was also supported by institutional start-up funds (to M. D. P.), by a scholars award from the V Foundation for Cancer Research (to M. D. P.), and by American Cancer Society Research Scholars Grant RSG-11-224-01-DMC (to M. D. P.).

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