REGULATION OF SAT1 pre- mRNA ALTERNATIVE SPLICING UPON DENGUE VIRUS INFECTION

POZZI, BERTA; GEBHARD, LEOPOLDO; IGLESIAS, GABRIEL; GAMARNIK, ANDREA V; SREBROW, ANABELLA

CABA

Simposio; FRONTERAS EN BIOCIENCIA 3; 2018

Recent studies carried out in Gamarnik and Srebrow laboratories allowed us to establish and report the first link between dengue virus infection and host cell splicing machinery. In RNA-seq experiments using human cultured cells infected with dengue, we observed an enrichment of intronic sequences at 24 and 36 hours post-infection. While this phenomenon was considered rare in mammals, it has been reported with increased frequency and mostly associated with human diseases. In addition, we found that viral infection leads to changes in alternative splicing of some genes known to have pro- or anti-viral functions (e.g., HNRNPDL, PHLDB2, POPDC3, PYCR1, SAT1 and WARS). In particular, we have noted that the transcript of SAT1 gene, of well-known antiviral action, evidences greater inclusion of exon 4 in infected cells, which leads to an mRNA isoform that is degraded by NMD (Non-sense Mediated Decay). SAT1 is a spermidine and spermine acetyl-transferase enzyme that, when induced by interferon, decreases the reservoir of these polyamines in the cell, limiting viral replication. Therefore, the increase of the mRNA isoform that is sensitive to degradation could represent a infection-triggered attenuation of the antiviral response. We intend to delve into the molecular mechanism responsible for this alternative splicing regulation of SAT1 pre-mRNA, as well as in other transcripts involved in the cellular response to infection.