Ubiquitin-dependent proteolytic control of SUMO conjugates.
Posttranslational protein modification with small ubiquitin-related modifier (SUMO) is an important regulatory mechanism implicated in many cellular processes, including several of biomedical relevance. We report that inhibition of the proteasome leads to accumulation of proteins that are simultaneously conjugated to both SUMO and ubiquitin in yeast and in human cells. A similar accumulation of such conjugates was detected in Saccharomyces cerevisiae ubc4 ubc5 cells as well as in mutants lacking two RING finger proteins, Ris1 and Hex3/Slx5-Slx8, that bind to SUMO as well as to the ubiquitin-conjugating enzyme Ubc4. In vitro, Hex3-Slx8 complexes promote Ubc4-dependent ubiquitylation. Together these data identify a previously unrecognized pathway that mediates the proteolytic down-regulation of sumoylated proteins. Formation of substrate-linked SUMO chains promotes targeting of SUMO-modified substrates for ubiquitin-mediated proteolysis. Genetic and biochemical evidence indicates that SUMO conjugation can ultimately lead to inactivation of sumoylated substrates by polysumoylation and/or ubiquitin-dependent degradation. Simultaneous inhibition of both mechanisms leads to severe phenotypic defects.
Uzunova
Kristina
K
Institute for Genetics, University of Cologne, Zülpicher Strasse 47, Cologne, Germany.
Göttsche
Kerstin
K
Miteva
Maria
M
Weisshaar
Stefan R
SR
Glanemann
Christoph
C
Schnellhardt
Marion
M
Niessen
Michaela
M
Scheel
Hartmut
H
Hofmann
Kay
K
Johnson
Erica S
ES
Praefcke
Gerrit J K
GJ
Dohmen
R Jürgen
RJ
D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination / Q000502:physiology*
D004268:DNA-Binding Proteins; D061988:Proteasome Inhibitors; D025842:SUMO-1 Protein; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C501306:Ubc4 protein, S cerevisiae; D044763:Ubiquitin-Conjugating Enzymes; C515574:Slx8 protein, S cerevisiae; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; C506745:ULS1 protein, S cerevisiae; D004265:DNA Helicases; C515573:Slx5 protein, S cerevisiae