[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Daou, Salima; Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, QC, H3C 3J7, Canada ; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, M5G 1X5, Canada
Barbour, Haithem; Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, QC, H3C 3J7, Canada
Ahmed, Oumaima; Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, QC, H3C 3J7, Canada
Masclef, Louis ; Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, QC, H3C 3J7, Canada
Baril, Caroline; Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, University of Montréal, Montréal, QC, H3T 1J4, Canada
Sen Nkwe, Nadine; Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, QC, H3C 3J7, Canada
Tchelougou, Daméhan ; Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, QC, H3C 3J7, Canada
Uriarte, Maxime ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, QC, H3C 3J7, Canada
Bonneil, Eric ; Institute for Research in Immunology and Cancer, Laboratory of Proteomics and Bioanalytical Mass Spectrometry, University of Montréal, Montréal, QC, H3T 1J4, Canada
Ceccarelli, Derek ; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, M5G 1X5, Canada
Mashtalir, Nazar; Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, QC, H3C 3J7, Canada
Tanji, Mika; University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, 96813, USA
Masson, Jean-Yves; CHU de Quebec Research Center (Oncology Axis), Laval University Cancer Research Center, 9 McMahon, Quebec, PQ, G1R 2J6, Canada
Thibault, Pierre; Institute for Research in Immunology and Cancer, Laboratory of Proteomics and Bioanalytical Mass Spectrometry, University of Montréal, Montréal, QC, H3T 1J4, Canada
Sicheri, Frank; Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, M5G 1X5, Canada
Yang, Haining; University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, 96813, USA
Carbone, Michele; University of Hawaii Cancer Center, University of Hawaii, Honolulu, HI, 96813, USA
Therrien, Marc; Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling, University of Montréal, Montréal, QC, H3T 1J4, Canada. marc.therrien@umontreal.ca ; Département de pathologie et biologie cellulaire, University of Montréal, Montréal, QC, H3C 3J7, Canada. marc.therrien@umontreal.ca
Affar, El Bachir; Maisonneuve-Rosemont Hospital Research Center and Department of Medicine, University of Montréal, Montréal, QC, H3C 3J7, Canada. el.bachir.affar@umontreal.ca
We thank Jürg Muller for insightful comments and reagents. We thank Diana Adjaoud, Ian Hammond-Martel, Pham My-An, and Erlinda Diaz Fernandez for technical assistance. This work was supported by grants from the Canadian Institutes of Health Research (CIHR) to E.B.A. (399244), a Foundation grant from the CIHR to M.T. (388023), a Foundation grant from the CIHR to J.Y.M. (388879), and grants from the Natural Sciences and Engineering Research Council of Canada (2015-2020) and Mesothelioma Applied Research Foundation (MARF) to E.B.A. E.B.A. is a senior scholar of the Fonds de la Recherche du Québec-Santé (FRQ-S). J.Y.M. is a Fonds de la Recherche du Québec-Santé (FRQ-S) research chair in genome stability . This work was supported by Department of Defense Grant No. CA150220 toH.Y. and M.C.; National Cancer Institute (NCI) GrantNo. R01 CA198138 to M.C.; the University of Hawaii Foundation, whichreceived unrestricted donations to support cancer and mesotheliomaresearch from: The Melohn family endowment (M.C.); HoneywellInternational (M.C.); The Riviera United 4-a Cure to M.C. and H.Y. S.D. has a Banting postdoctoral fellowship. H.B. has a PhD scholarship from the Ministry of Higher Education and Scientific Research of Tunisia and the Cole Foundation. O.A. has a MSc scholarship from the The Canadian Francophonie Scholarship Program. The Institute for Research in Immunology and Cancer (IRIC) receives infrastructure support from Genome Canada and Génome Québec, IRICoR, the Canadian Foundation for Innovation, and the Fonds de Recherche du Québec - Santé (FRQS).
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