Monoubiquitination of ASXLs controls the deubiquitinase activity of the tumor suppressor BAP1

Salima Daou, Haithem Barbour, Oumaima Ahmed, Louis Masclef, Caroline Baril, Nadine Nkwe, Daméhan Tchelougou, Maxime Uriarte, Eric Bonneil, Derek Ceccarelli, Nazar Mashtalir, Mika Tanji, Jean-Yves Masson, Pierre Thibault, Frank Sicheri, Haining Yang, Michele Carbone, Marc Therrien () and El Bachir Affar ()
Additional contact information
Salima Daou: University of Montréal
Haithem Barbour: University of Montréal
Oumaima Ahmed: University of Montréal
Louis Masclef: University of Montréal
Caroline Baril: University of Montréal
Nadine Nkwe: University of Montréal
Daméhan Tchelougou: University of Montréal
Maxime Uriarte: University of Montréal
Eric Bonneil: University of Montréal
Derek Ceccarelli: Sinai Health System
Nazar Mashtalir: University of Montréal
Mika Tanji: University of Hawaii Cancer Center, University of Hawaii
Jean-Yves Masson: Laval University Cancer Research Center, 9 McMahon
Pierre Thibault: University of Montréal
Frank Sicheri: Sinai Health System
Haining Yang: University of Hawaii Cancer Center, University of Hawaii
Michele Carbone: University of Hawaii Cancer Center, University of Hawaii
Marc Therrien: University of Montréal
El Bachir Affar: University of Montréal

Nature Communications, 2018, vol. 9, issue 1, 1-21

Abstract: Abstract The tumor suppressor and deubiquitinase (DUB) BAP1 and its Drosophila ortholog Calypso assemble DUB complexes with the transcription regulators Additional sex combs-like (ASXL1, ASXL2, ASXL3) and Asx respectively. ASXLs and Asx use their DEUBiquitinase ADaptor (DEUBAD) domain to stimulate BAP1/Calypso DUB activity. Here we report that monoubiquitination of the DEUBAD is a general feature of ASXLs and Asx. BAP1 promotes DEUBAD monoubiquitination resulting in an increased stability of ASXL2, which in turn stimulates BAP1 DUB activity. ASXL2 monoubiquitination is directly catalyzed by UBE2E family of Ubiquitin-conjugating enzymes and regulates mammalian cell proliferation. Remarkably, Calypso also regulates Asx monoubiquitination and transgenic flies expressing monoubiquitination-defective Asx mutant exhibit developmental defects. Finally, the protein levels of ASXL2, BAP1 and UBE2E enzymes are highly correlated in mesothelioma tumors suggesting the importance of this signaling axis for tumor suppression. We propose that monoubiquitination orchestrates a molecular symbiosis relationship between ASXLs and BAP1.

Date: 2018
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DOI: 10.1038/s41467-018-06854-2

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