Targeting SUMO E1 to ubiquitin ligases: a viral strategy to counteract sumoylation.
SUMO-1 (small ubiquitin-related modifier-1) is a ubiquitin-like family member that is conjugated to its substrates through three discrete enzymatic steps, activation (involving the E1 enzyme (SAE1/SAE2)), conjugation (involving the E2 enzyme), and substrate modification (through the cooperation of the E2 and E3 protein ligases). The adenoviral protein Gam1 inactivates E1, both in vitro and in vivo, followed by SAE1/SAE2 degradation. We have shown here that Gam1 possesses a C-terminal SOCS domain that allows its interaction with two cellular cullin RING (really interesting new gene) ubiquitin ligases. We demonstrate that Gam1 is necessary for the recruitment of SAE1/SAE2 into Cul2/5-EloB/C-Roc1 ubiquitin ligase complexes and for subsequent SAE1 ubiquitylation and degradation. The degradation of SAE2 is not tightly related to Gam1 but is a consequent effect of SAE1 disappearance. These results reveal the mechanism by which a viral protein inactivates and subsequently degrades an essential cellular enzyme, arresting a key regulatory pathway.
Boggio
Roberto
R
Department of Experimental Oncology, European Institute of Oncology, 20141 Milan, Italy.
Passafaro
Alfonso
A
Chiocca
Susanna
S
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D025681:Fowl adenovirus A / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
C105052:CELO protein, adenovirus; C105153:CUL2 protein, human; C496871:CUL5 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D009097:Multienzyme Complexes; C479529:RBX1 protein, human; D025842:SUMO-1 Protein; C470301:UBA2 protein, human; D014764:Viral Proteins; C470299:SAE1 protein, human; D044764:Ubiquitin-Activating Enzymes