title: Inhibition of Ubc13-mediated Ubiquitination by GPS2 Regulates Multiple Stages of B Cell Development.
abstract: Non-proteolytic ubiquitin signaling mediated by Lys63ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNFα signaling and lipid metabolism in the adipose tissue through modulation of Lys63ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmedin vivoby B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells.
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lentucci
authors.affiliation: the Flow Cytometry Core Facility, Boston University School of Medicine, Boston, Massachusetts 02118 and.|Microbiology, and.
authors.forename: Anna C
authors.identifier: 0000-0001-7967-6254
authors.initials: AC
authors.lastname: Belkina
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Carly T
authors.initials: CT
authors.lastname: Cederquist
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Michelle
authors.initials: M
authors.lastname: Chan
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Holly E
authors.initials: HE
authors.lastname: Johnson
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Sherry
authors.initials: S
authors.lastname: Prasad
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Amanda
authors.initials: A
authors.lastname: Lopacinski
authors.affiliation: Microbiology, and.
authors.forename: Barbara S
authors.identifier: 0000-0001-5647-5740
authors.initials: BS
authors.lastname: Nikolajczyk
authors.affiliation: Medicine and.
authors.forename: Stefano
authors.identifier: 0000-0002-9376-0660
authors.initials: S
authors.lastname: Monti
authors.affiliation: the Flow Cytometry Core Facility, Boston University School of Medicine, Boston, Massachusetts 02118 and.|Microbiology, and.
authors.forename: Jennifer
authors.identifier: 0000-0002-0941-5582
authors.initials: J
authors.lastname: Snyder-Cappione
authors.affiliation: the Department of Pediatrics, Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Bogdan
authors.identifier: 0000-0002-3797-8171
authors.initials: B
authors.lastname: Tanasa
authors.affiliation: From the Departments of Biochemistry.
authors.forename: M Dafne
authors.identifier: 0000-0003-4591-3447
authors.initials: MD
authors.lastname: Cardamone
authors.affiliation: From the Departments of Biochemistry, vperissi@bu.edu.
authors.forename: Valentina
authors.identifier: 0000-0002-3716-0003
authors.initials: V
authors.lastname: Perissi
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology*; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D015398:Signal Transduction; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors*; D054875:Ubiquitination
chemical_list: C572597:GPS2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes
keywords: Notch pathway; development; toll-like receptor (TLR); ubiquitin; ubiquitin-conjugating enzyme (E2 enzyme)