There are several types of unwanted RNA in the cytoplasm of a cell including viral RNAs, endogenous retroelements, mitochondrial RNAs and mRNAs with processing errors. When a cell detects these RNAs, it can target them for degradation, inhibit their translation or induce signal transduction pathways that activate pro-inflammatory and antiviral gene expression. Global RNA degradation, inhibition of cap-dependent translation and cell death pathways can also be activated. If these RNAs accumulate in the cytoplasm, they lead to several pathologies including autoimmune and neurodegenerative diseases.
Unwanted RNAs are detected by reader proteins that bind a specific molecular pattern. This pattern can be a linear RNA sequence, RNA structure or a combination of these elements. RNA modifications, such as N6-methyladenosine (m6A), can also promote or inhibit binding of reader proteins to RNA. Unwanted RNAs are enriched in dinucleotides (e.g. CpG or UpA), long exons, retained introns, double stranded RNA structures or the absence of RNA modifications (e.g. the 5’ cap structure on mRNAs). The full spectrum of reader proteins that recognise these patterns is unclear and how they recruit effector proteins for RNA decay, translation inhibition or signalling is poorly understood.
The Swanson lab is characterising how reader proteins recognise unwanted RNAs in the cytoplasm and regulate these transcripts, with a focus on viral RNAs and endogenous retroelements. One of the reader proteins that we are studying is zinc finger antiviral protein (ZAP), which restricts several RNA viruses that cause human disease as well as endogenous retroelements. ZAP interacts with other cellular proteins to form the ZAP antiviral system, and we are characterising two additional components of this system: the E3 ubiquitin ligase TRIM25, and the endonuclease KHNYN. In addition, we are studying how m6A RNA modifications modulate gene expression and viral replication. The Swanson lab uses a variety of experimental approaches to answer these questions including molecular biology and virology techniques, transcriptomics, proteomics and microscopy. Overall, we are characterising how cellular proteins recognise specific patterns in viral or cellular RNAs to target them for degradation or inhibit their translation to prevent them from promoting autoimmune or neurodegenerative diseases.
