‘Self’ RNAs & Interferons

We have a long-standing interest in the interplay between pathogens and host SUMOylation. SUMO proteins are small ubiquitin-like modifiers that can be reversibly attached to other proteins to alter their function, and play critical roles in cellular activities such as transcription, DNA damage responses, and interferon (IFN) action (reviewed in Everett, Boutell & Hale, Nature Reviews Microbiology, 2013).

Previously, we applied large-scale proteomic approaches to identify cellular proteins that change in SUMOylation during virus infection, as well as during the IFN response (Domingues et al., Cell Reports, 2015; Schmidt et al., PNAS, 2019). These resources have proved to be an important starting point for many projects in the laboratory, including those relating to virus host-range mechanisms (Domingues et al, Cell Reports, 2017;Domingues et al., Nature Communications, 2019).

In one follow-up, we detailed evidence to suggest that loss of SUMO-modified TRIM28 is a previously undescribed host response to influenza virus infection leading to transcription of immunostimulatory ‘self’ RNAs that activate antiviral IFN responses  (Schmidt et al., PNAS, 2019). Such a mechanism blurs the canonical view that a host must strictly discriminate between ‘self’ and ‘non-self’ RNAs to defend against invading pathogens and prevent autoimmune reactions (reviewed inHale, Current Opinion in Virology, 2022). We are actively investigating the viral triggers and cellular machinery involved in this process at the molecular level, with aims to delineate how presence of immunostimulatory ‘self’ RNAs can be detected by the host cell and modulated by pathogenic viruses (e.g. Lork et al., bioRxiv, 2024).

Figure legend: An infection-triggered SUMO switch in TRIM28 orchestrates endogenous retroelements to stimulate host innate immunity (Schmidt et al., PNAS, 2019).