A novel and human-specific CD46-SP1 axis regulates gene transcription and HIV expression in CD4+ T cells 2574

Abstract Description Signaling events mediated by the human-specific complement regulator and receptor CD46 are vital coordinators of the metabolic gene program underlying normal monocyte activation and Th1 immunity. Perturbations in CD46 signals therefore are associated with several disease states, including recurrent infections, autoimmunity, and cancer. The molecular mechanism by which CD46 controls cellular gene transcription is unknown. Here, we demonstrate that the cleaved, intracellular signaling domain of CD46 interacts with the transcription factor specificity protein 1 (Sp1) in human CD4 T cells to dynamically modulate Sp1–DNA interactions. Specifically, CD46–Sp1-controlled gene programs sustain naive CD4 T cell survival through tonic suppression of the death Caspase-3 machinery and, concurrently, enable initiation of the IFN-γ production pathways. Furthermore, the CD46–Sp1 axis also restrains transcription of integrated human deficiency virus type 1 (HIV) in human CD4 T cells, indicating an unexpected role for CD46 in HIV infection. Our findings add important insights into human-specific aspects of complement and T cell biology and provide a tangible opening to define novel physiological and pathophysiological roles of CD46 across cells and diseases. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)