title: The cyclomodulin cycle inhibiting factor (CIF) alters cullin neddylation dynamics.
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.
authors.affiliation: Signal Transduction Program, NCI-designated Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.
authors.forename: Tasha B
authors.initials: TB
authors.lastname: Toro
authors.forename: Julia I
authors.initials: JI
authors.lastname: Toth
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Petroski
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D000075686:COP9 Signalosome Complex; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D000075687:NEDD8 Protein; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D044842:Cullin Proteins; C502135:Dcn1 protein, S cerevisiae; D046912:Multiprotein Complexes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D029701:Saccharomyces cerevisiae Proteins; D014452:Ubiquitins; D005973:Glutamine; D018698:Glutamic Acid; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex
keywords: CIF; Cullin-RING Ubiquitin Ligases; NEDD8; Signal Transduction; Ubiquitin; Ubiquitin Ligase; Ubiquitin-like Proteins; Ubiquitination; Yeast