C. elegans CAND-1 regulates cullin neddylation, cell proliferation and morphogenesis in specific tissues.
Cullin-RING ubiquitin ligases (CRLs) are critical regulators of multiple developmental and cellular processes in eukaryotes. CAND1 is a biochemical inhibitor of CRLs, yet has been shown to promote CRL activity in plant and mammalian cells. Here we analyze CAND1 function in the context of a developing metazoan organism. Caenorhabditis elegans CAND-1 is capable of binding to all of the cullins, and we show that it physically interacts with CUL-2 and CUL-4 in vivo. The covalent attachment of the ubiquitin-like protein Nedd8 is required for cullin activity in animals and plants. In cand-1 mutants, the levels of the neddylated isoforms of CUL-2 and CUL-4 are increased, indicating that CAND-1 is a negative regulator of cullin neddylation. cand-1 mutants are hypersensitive to the partial loss of cullin activity, suggesting that CAND-1 facilitates CRL functions. cand-1 mutants exhibit impenetrant phenotypes, including developmental arrest, morphological defects of the vulva and tail, and reduced fecundity. cand-1 mutants share with cul-1 and lin-23 mutants the phenotypes of supernumerary seam cell divisions, defective alae formation, and the accumulation of the SCF(LIN-23) target the glutamate receptor GLR-1. The observation that cand-1 mutants have phenotypes associated with the loss of the SCF(LIN-23) complex, but lack phenotypes associated with other specific CRL complexes, suggests that CAND-1 is differentially required for the activity of distinct CRL complexes.
Bosu
Dimple R
DR
Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA.
Feng
Hui
H
Min
Kyoengwoo
K
Kim
Youngjo
Y
Wallenfang
Matthew R
MR
Kipreos
Edward T
ET
D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology*; D029742:Caenorhabditis elegans Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000378:metabolism; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D009024:Morphogenesis; D009154:Mutation; D010641:Phenotype; D020033:Protein Isoforms; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
C552422:CAND-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C475682:Cul-4 protein, C elegans; D044842:Cullin Proteins; D044783:F-Box Proteins; D020033:Protein Isoforms; C491027:cul-2 proteins, C elegans; C418507:lin-23 protein, C elegans; D044767:Ubiquitin-Protein Ligases; D008025:Ligases