CD38 restrains the activity of extracellular cGAMP in a model of multiple myeloma

• DOI: 10.1016/j.isci.2024.109814
• Publication Date: 2024-04-25T15:31:56Z
• Authors: Lorenzo Cuollo; Samuele Di Cristo...; Annamaria Sandome...; Emanuela Iaccarino; Angela Oliver; Alessandra Zingoni; Marco Cippitelli; Cinzia Fionda; Sara Petillo; Andrea Kosta; Valentina Tassinari; Maria Teresa Petr...; Francesca Fazio; Menotti Ruvo; Angela Santoni; Domenico Raimondo; Alessandra Soriani
• Keywords: 0301 basic medicine; Cell biology; In silico biology; Molecular biology; Science; Q; Article; Components of the immune system; 03 medical and health sciences; cGAMP, CD38, Myeloma; cGamp; Biochemical mechanism; mieloma mulptiple; Cancer

2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) is the endogenous agonist of STING; as such, cGAMP has powerful immunostimulatory activity, due to its capacity to stimulate type I interferon-mediated immunity. Recent evidence indicates that cancer cells, under certain conditions, can release cGAMP extracellularly, a phenomenon currently considered important for therapeutic responses and tumor rejection. Nonetheless, the mechanisms that regulate cGAMP activity in the extracellular environment are still largely unexplored. In this work, we collected evidence demonstrating that CD38 glycohydrolase can inhibit extracellular cGAMP activity through its direct binding. We firstly used different cell lines and clinical samples to demonstrate a link between CD38 and extracellular cGAMP activity; we then performed extensive in silico molecular modeling and cell-free biochemical assays to show a direct interaction between the catalytic pocket of CD38 and cGAMP. Altogether, our findings expand the current knowledge about the regulation of cGAMP activity.