Elevated levels of intracellular RNA lariats suppress the antiviral response

Duan, C.; Buerer, L.; Bowers, C.; Taggart, A. J.; OBrien, M. H.; Gunasekera, S.; Lin, C.-L.; Wang, J.; Staley, J. P.; Fredericks, A. M.; Monaghan, S. F.; Welch, A.; Clark, N. E.; Gao, D.; Marr, N.; Zhang, S.-Y.; Casanova, J.-L.; Fairbrother, W. G.

doi:10.1101/2024.12.07.627371

bioRxiv · 10.1101/2024.12.07.627371

Elevated levels of intracellular RNA lariats suppress the antiviral response

Duan, C.·Buerer, L.·Bowers, C.·Taggart, A. J.·OBrien, M. H.·Gunasekera, S.·Lin, C.-L.·Wang, J.·Staley, J. P.·Fredericks, A. M.·Monaghan, S. F.·Welch, A.·Clark, N. E.·Gao, D.·Marr, N.·Zhang, S.-Y.·Casanova, J.-L.·Fairbrother, W. G.

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Abstract

Recent studies report the genetic loss of the lariat debranching enzyme (DBR1) activity increases susceptibility to viral infection. Here, we show that more than 25% of human introns contain large hairpin structures created by the folding of two Alu elements inserted in opposite orientation. In wildtype cells, this large reservoir of endogenous dsRNA is efficiently degraded. In DBR1-null cells, lariats accumulate in the cytosol and dsRNA becomes enriched. We demonstrate how the chronic exposure to these lariats attenuates the dsRNA sensors, reducing the response of the MDA5, RIG-I, RNase L and PKR sensing pathways. We observe evidence for both attenuation and endogenous dsRNA in anti-viral response and viral evasion. Lariats are transiently elevated during infection (e.g. HSV-1, influenza, KSHV). The HSV-1 genome expresses multiple, stable lariats that may attenuate dsRNA sensors during latency. HIGHLIGHTSO_LIIntronic inverted repeat Alu elements constitute largest source of endogenous dsRNA. C_LIO_LIIn the absence of DBR1, lariats accumulate in the cytoplasm and form dsRNA. C_LIO_LIChronic exposure to endogenous dsRNA in a DBR1-depleted environment desensitizes the dsRNA sensing pathway. C_LIO_LIICP0 intron 1 of HSV-1 has a highly-structured stable lariat. C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/627371v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@3698bborg.highwire.dtl.DTLVardef@654727org.highwire.dtl.DTLVardef@1229245org.highwire.dtl.DTLVardef@b10622_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Duan, C., Buerer, L., Bowers, C., Taggart, A. J., OBrien, M. H., Gunasekera, S., Lin, C.-L., Wang, J., Staley, J. P., Fredericks, A. M., Monaghan, S. F., Welch, A., Clark, N. E., Gao, D., Marr, N., Zhang, S.-Y., Casanova, J.-L., Fairbrother, W. G.. 2024-12-08. Elevated levels of intracellular RNA lariats suppress the antiviral response. https://doi.org/10.1101/2024.12.07.627371

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