Innate immune regulation
The innate immune response constitutes the first host response against invading viruses and shapes the following adaptive response. The production of inflammatory mediators and interferon is essential to mount an adequate anti-viral response and this is controlled by particular cellular transcription factors (i.e. NF-kB, IRF3, AP-1). We are interested in how the activation of these factors is orchestrated at the molecular level and what consequences this has on the overall host response and viral pathogenesis.
Our work has recently uncovered a novel regulatory mechanism in the control of inflammatory responses (Georgana et al. 2020, Frontiers in Immunology). Cullin-5 is a member of the cullin family of E3 ubiquitin ligases, a family of scaffold proteins that assemble multi-protein complexes able to ubiquitylate substrates. The specificity of the system towards a certain substrate is determined by a number of substrate adaptors. We developed a high-throughput screening system to evaluate the role of Cullin-5 adaptors in the control of NF-kB activation. Our work revealed the adaptor SPSB1 as a potent negative regulator of p65 and transcription of NF-kB dependent genes including the expression of pro-inflammatory cytokines.