Abstract
GNA13, encoding one of the G protein alpha subunits of heterotrimeric G proteins that transduce signals of G protein-coupled receptors (GPCR), is frequently mutated in germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) with poor prognostic outcomes. Due to the “undruggable” nature of GNA13, targeted therapy for these patients is not available. In this study, we found that palmitoylation of GNA13 not only regulates its plasma membrane localization, but also regulates GNA13’s stability. It is essential for the tumor suppressor function of GNA13 in GCB-DLBCL cells. Interestingly, GNA13 negatively regulates BCL2 expression in GCB-DLBCL cells in a palmitoylation-dependent manner. Consistently, BCL2 inhibitors were found to be effective in killing GNA13-deficient GCB-DLBCL cells in a cell-based chemical screen. Furthermore, we demonstrate that inactivating GNA13 by targeting its palmitoylation enhanced the sensitivity of GCB-DLBCL to the BCL2 inhibitor. These studies indicate that the loss-of-function mutation of GNA13 is a biomarker for BCL2 inhibitor therapy of GCB-DLBCL and that GNA13 palmitoylation is a potential target for combination therapy with BCL2 inhibitors to treat GCB-DLBCL with wild-type GNA13.
Highlights
GNA13 encodes one of the alpha subunits (GNA13/Gα13) of the heterotrimeric G proteins that transduce signals of G protein-coupled receptors (GPCR)
GNA13 regulates its plasma membrane localization, and regulates GNA13’s stability. It is essential for the tumor suppressor function of GNA13 in GC B-cell-like (GCB)-diffuse large B-cell lymphoma (DLBCL) cells
We found that GNA13 negatively regulates BCL2 expression in GCBDLBCL in a palmitoylation-dependent manner
Summary
GNA13 encodes one of the alpha subunits Gα13) of the heterotrimeric G proteins that transduce signals of G protein-coupled receptors (GPCR). It is expressed in various tissues, including lymphoid, vascular, and bone tissues in embryos and adults. GNA13 is classified into the Gα12/13 subfamily and highly homologous to GNA121, GNA13 has unique functions. It has been shown to play critical roles in localization of germinal center (GC) B cells[2], angiogenesis[3], female fertility[4,5], bone homeostasis[6], and platelet activation[7,8]. Recurrent mutations in the GNA13 gene have been identified in multiple tumor types.
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