Autodeubiquitination protects the tumor suppressor BAP1 from cytoplasmic sequestration mediated by the atypical ubiquitin ligase UBE2O.
The tumor suppressor BAP1 interacts with chromatin-associated proteins and regulates cell proliferation, but its mechanism of action and regulation remain poorly defined. We show that the ubiquitin-conjugating enzyme UBE2O multi-monoubiquitinates the nuclear localization signal of BAP1, thereby inducing its cytoplasmic sequestration. This activity is counteracted by BAP1 autodeubiquitination through intramolecular interactions. Significantly, we identified cancer-derived BAP1 mutations that abrogate autodeubiquitination and promote its cytoplasmic retention, indicating that BAP1 autodeubiquitination ensures tumor suppression. The antagonistic relationship between UBE2O and BAP1 is also observed during adipogenesis, whereby UBE2O promotes differentiation and cytoplasmic localization of BAP1. Finally, we established a putative targeting consensus sequence of UBE2O and identified numerous chromatin remodeling factors as potential targets, several of which tested positive for UBE2O-mediated ubiquitination. Thus, UBE2O defines an atypical ubiquitin-signaling pathway that coordinates the function of BAP1 and establishes a paradigm for regulation of nuclear trafficking of chromatin-associated proteins.
Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC H1T 2M4, Canada.
Nazar
N
Mashtalir
Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC H1T 2M4, Canada.
Salima
S
Daou
Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC H1T 2M4, Canada.
Haithem
H
Barbour
Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC H1T 2M4, Canada.
Nadine N
NN
Sen
Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC H1T 2M4, Canada.
Jessica
J
Gagnon
Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC H1T 2M4, Canada.
Ian
I
Hammond-Martel
Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC H1T 2M4, Canada.
Haider H
HH
Dar
Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, University of Montréal, Montréal, QC H3T 1J4, Canada.
Marc
M
Therrien
Maisonneuve-Rosemont Hospital Research Center, Department of Medicine, University of Montréal, Montréal, QC H1T 2M4, Canada. Electronic address: aelbachir.hmr@ssss.gouv.qc.ca.
El Bachir
el B
Affar
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D016384:Consensus Sequence; D003593:Cytoplasm / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics; D019913:Nuclear Localization Signals; D021381:Protein Transport; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism*; D054875:Ubiquitination
C400134:BAP1 protein, human; D019913:Nuclear Localization Signals; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C471545:UBE2A protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043222:Ubiquitin Thiolesterase