Molecular Mechanisms Regulating Type I and III Interferon Signaling

Abstract

Interferons (IFNs) are central to host defense against viral infection. A class of cytokines produced in response to pathogens, IFNs signal through one of three cell-surface receptors: type I, type II or type III. These receptors activate JAK-STAT pathways to induce transcription of hundreds of IFN- stimulated genes that are involved in viral clearance. Precise regulation of these pathways is essential for a controlled innate immune response. Downregulation of IFN signaling renders a host hyper-susceptible to viral infection, while chronic upregulation of IFN signaling leads to autoinflammatory diseases known as interferonopathies. Although much work has been done to understand this regulation, IFN signaling forms a complex circuit with many unanswered questions (Chapter 1). The work presented in this dissertation addresses three key areas of study: (i) the development of synthetic tools, including receptors, biosensors, and reporters, to study IFN signaling with greater precision (Chapter 2); (ii) new mechanistic insights into the regulation of type I and III IFN signaling differences via their receptors, in which we show that motifs within IFN receptor intracellular domains encode signal strength (Chapter 3); and (iii) elucidation of differential requirements for TYK2 between type I and III IFN receptors, leading to proposed alternatives to the current canonical model of heterodimeric IFN receptor assembly (Chapter 4).