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

被引：48

作者：

Daou, Salima ^{[1
,2
,3
]}

Barbour, Haithem ^{[1
,2
]}

Ahmed, Oumaima ^{[1
,2
]}

Masclef, Louis ^{[1
,2
]}

Baril, Caroline ^{[4
]}

Sen Nkwe, Nadine ^{[1
,2
]}

Tchelougou, Damehan ^{[1
,2
]}

Uriarte, Maxime ^{[1
,2
]}

Bonneil, Eric ^{[5
]}

Ceccarelli, Derek ^{[3
]}

Mashtalir, Nazar ^{[1
,2
]}

Tanji, Mika ^{[6
]}

Masson, Jean-Yves ^{[7
]}

Thibault, Pierre ^{[5
]}

Sicheri, Frank ^{[3
]}

Yang, Haining ^{[6
]}

Carbone, Michele ^{[6
]}

Therrien, Marc ^{[4
,8
]}

Affar, El Bachir ^{[1
,2
]}

机构：

[1] Univ Montreal, Maisonneuve Rosemont Hosp, Res Ctr, Montreal, PQ H3C 3J7, Canada

[2] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada

[3] Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada

[4] Univ Montreal, Inst Res Immunol & Canc, Lab Intracellular Signaling, Montreal, PQ H3T 1J4, Canada

[5] Univ Montreal, Inst Res Immunol & Canc, Lab Prote & Bioanalyt Mass Spectrometry, Montreal, PQ H3T 1J4, Canada

[6] Univ Hawaii, Canc Ctr, Honolulu, HI 96813 USA

[7] Laval Univ, Canc Res Ctr, CHU Quebec, Res Ctr Oncol Axis, 9 McMahon, Quebec City, PQ G1R 2J6, Canada

[8] Univ Montreal, Dept Pathol & Biol Cellulaire, Montreal, PQ H3C 3J7, Canada

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

加拿大健康研究院; 加拿大自然科学与工程研究理事会;

关键词：

GROUP GENES; E3; LIGASE; ACTIVATION; PROTEASOME; UBIQUITIN; ENZYME; UCH37; DROSOPHILA; POLYCOMB; COMPLEX;

D O I：

10.1038/s41467-018-06854-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：21