Rhes, a physiologic regulator of sumoylation, enhances cross-sumoylation between the basic sumoylation enzymes E1 and Ubc9.
We recently reported that the small G-protein Rhes has the properties of a SUMO-E3 ligase and mediates mutant huntingtin (mHtt) cytotoxicity. We now demonstrate that Rhes is a physiologic regulator of sumoylation, which is markedly reduced in the corpus striatum of Rhes-deleted mice. Sumoylation involves activation and transfer of small ubiquitin-like modifier (SUMO) from the thioester of E1 to the thioester of Ubc9 (E2) and final transfer to lysines on target proteins, which is enhanced by E3s. We show that E1 transfers SUMO from its thioester directly to lysine residues on Ubc9, forming isopeptide linkages. Conversely, sumoylation on E1 requires transfer of SUMO from the thioester of Ubc9. Thus, the process regarded as "autosumoylation" reflects intermolecular transfer between E1 and Ubc9, which we designate "cross-sumoylation." Rhes binds directly to both E1 and Ubc9, enhancing cross-sumoylation as well as thioester transfer from E1 to Ubc9.
Subramaniam
Srinivasa
S
Solomon H. Snyder Department of Neuroscience, Departments of Pharmacology and Molecular Sciences and Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Mealer
Robert G
RG
Sixt
Katherine M
KM
Barrow
Roxanne K
RK
Usiello
Alessandro
A
Snyder
Solomon H
SH
D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D025841:Small Ubiquitin-Related Modifier Proteins; D005973:Glutamine; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D019204:GTP-Binding Proteins; C488189:Rasd2 protein, mouse; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D008239:Lysine; D003545:Cysteine