RSUME, a small RWD-containing protein, enhances SUMO conjugation and stabilizes HIF-1alpha during hypoxia.
SUMO conjugation to proteins is involved in the regulation of diverse cellular functions. We have identified a protein, RWD-containing sumoylation enhancer (RSUME), that enhances overall SUMO-1, -2, and -3 conjugation by interacting with the SUMO conjugase Ubc9. RSUME increases noncovalent binding of SUMO-1 to Ubc9 and enhances Ubc9 thioester formation and SUMO polymerization. RSUME enhances the sumoylation of IkB in vitro and in cultured cells, leading to an inhibition of NF-kB transcriptional activity. RSUME is induced by hypoxia and enhances the sumoylation of HIF-1alpha, promoting its stabilization and transcriptional activity during hypoxia. Disruption of the RWD domain structure of RSUME demonstrates that this domain is critical for RSUME action. Together, these findings point to a central role of RSUME in the regulation of sumoylation and, hence, several critical regulatory pathways in mammalian cells.
Carbia-Nagashima
Alberto
A
Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
Gerez
Juan
J
Perez-Castro
Carolina
C
Paez-Pereda
Marcelo
M
Silberstein
Susana
S
Stalla
Günter K
GK
Holsboer
Florian
F
Arzt
Eduardo
E
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009928:Organ Specificity; D011485:Protein Binding; D025842:SUMO-1 Protein / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; C525338:RWDD3 protein, human; D025842:SUMO-1 Protein; C117909:SUMO2 protein, human; C492189:SUMO3 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D014452:Ubiquitins; D044763:Ubiquitin-Conjugating Enzymes; D051550:I-kappa B Kinase; D000098843:Ubiquitin-Conjugating Enzyme UBC9