CD38 restrains the activity of extracellular cGAMP in a model of multiple myeloma
Lorenzo Cuollo,
Samuele Di Cristofano,
Annamaria Sandomenico,
Emanuela Iaccarino,
Angela Oliver,
Alessandra Zingoni,
Marco Cippitelli,
Cinzia Fionda,
Sara Petillo,
Andrea Kosta,
Valentina Tassinari,
Maria Teresa Petrucci,
Francesca Fazio,
Menotti Ruvo,
Angela Santoni,
Domenico Raimondo,
Alessandra Soriani
Affiliations
Lorenzo Cuollo
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
Samuele Di Cristofano
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
Annamaria Sandomenico
Institute of Biostructures and Bioimaging, CNR, Naples, Italy
Emanuela Iaccarino
Institute of Biostructures and Bioimaging, CNR, Naples, Italy
Angela Oliver
Institute of Biostructures and Bioimaging, CNR, Naples, Italy; University of Campania “Luigi Vanvitelli”, Caserta, Italy
Alessandra Zingoni
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
Marco Cippitelli
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
Cinzia Fionda
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
Sara Petillo
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
Andrea Kosta
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
Valentina Tassinari
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy
Maria Teresa Petrucci
Hematology, Department of Translational and Precision Medicine Azienda Policlinico Umberto I, Sapienza-Rome, Italy
Francesca Fazio
Hematology, Department of Translational and Precision Medicine Azienda Policlinico Umberto I, Sapienza-Rome, Italy
Menotti Ruvo
Institute of Biostructures and Bioimaging, CNR, Naples, Italy
Angela Santoni
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy
Domenico Raimondo
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy; Corresponding author
Alessandra Soriani
Department of Molecular Medicine, Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Rome, Italy; Corresponding author
Summary: 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.
