SUMO Signaling by Hypoxic Inactivation of SUMO-Specific Isopeptidases.
Post-translational modification of proteins with ubiquitin-like SUMO modifiers is a tightly regulated and highly dynamic process. The SENP family of SUMO-specific isopeptidases comprises six cysteine proteases. They are instrumental in counterbalancing SUMO conjugation, but their regulation is not well understood. We demonstrate that in hypoxic cell extracts, the catalytic activity of SENP family members, in particular SENP1 and SENP3, is inhibited in a rapid and fully reversible process. Comparative mass spectrometry from normoxic and hypoxic cells defines a subset of hypoxia-induced SUMO1 targets, including SUMO ligases RanBP2 and PIAS2, glucose transporter 1, and transcriptional regulators. Among the most strongly induced targets, we identified the transcriptional co-repressor BHLHE40, which controls hypoxic gene expression programs. We provide evidence that SUMOylation of BHLHE40 is reversed by SENP1 and contributes to transcriptional repression of the metabolic master regulator gene PGC-1α. We propose a pathway that connects oxygen-controlled SENP activity to hypoxic reprogramming of metabolism.
Institute of Biochemistry II, Goethe University, Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Kathrin
K
Kunz
Institute of Biochemistry II, Goethe University, Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Kristina
K
Wagner
Institute of Biochemistry II, Goethe University, Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Luca
L
Mendler
Institute of Biochemistry II, Goethe University, Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Soraya
S
Hölper
Institute of Biochemistry I, Goethe University, Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
Nathalie
N
Dehne
Institute of Biochemistry II, Goethe University, Medical School, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Electronic address: ste.mueller@em.uni-frankfurt.de.
Stefan
S
Müller
D055162:Biocatalysis; D019759:Carbon-Nitrogen Lyases / Q000378:metabolism*; D015687:Cell Hypoxia; D056970:Co-Repressor Proteins / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D015398:Signal Transduction; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D013379:Substrate Specificity; D058207:Sumoylation
D056970:Co-Repressor Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; C499718:SENP3 protein, human; D019759:Carbon-Nitrogen Lyases; C034300:isopeptidase
SENP; SUMO; SUMO isopeptidase; hypoxia; proteomics