Double-stranded RNA responses, neoantigen presentation and suppression of hepatocellular carcinoma through NMD inhibition via endonuclease SMG6

Arpa, E. S.; Ricci, V.; Shapiro, I. E.; Jokic, M.; Gonzalez Menendez, I.; Quintanilla-Fend, L.; Benechet, A. P.; Rehwinkel, J.; Luther, S. A.; Bassani-Sternberg, M.; Gatfield, D.

doi:10.1101/2025.01.13.632668

bioRxiv · 10.1101/2025.01.13.632668

Double-stranded RNA responses, neoantigen presentation and suppression of hepatocellular carcinoma through NMD inhibition via endonuclease SMG6

Arpa, E. S.·Ricci, V.·Shapiro, I. E.·Jokic, M.·Gonzalez Menendez, I.·Quintanilla-Fend, L.·Benechet, A. P.·Rehwinkel, J.·Luther, S. A.·Bassani-Sternberg, M.·Gatfield, D.

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Abstract

Nonsense-mediated mRNA decay (NMD) eliminates aberrant transcripts to maintain transcriptome integrity, yet its broader physiological roles remain incompletely defined. Here, using a liver-specific, inducible mouse model, we selectively inactivate the endonuclease SMG6 - the terminal effector of NMD - in a genetic model of hepatocellular carcinoma (HCC). SMG6 loss completely prevents tumour development and triggers robust innate and adaptive immune responses. Mechanistically, SMG6 inactivation causes the cytoplasmic accumulation of endogenous double-stranded RNAs (dsRNAs), leading to type I interferon induction via the dsRNA sensor MDA5 and revealing an unexpected physiological role for NMD in maintaining dsRNA homeostasis. In parallel, stabilisation and translation of normally degraded transcripts generate non-canonical MHC-I-presented peptides that elicit potent CD8+ T-cell responses. These findings identify SMG6-dependent NMD as a central gatekeeper that restrains dsRNA-driven antiviral signalling and suppresses immunogenic transcript expression. Our work establishes selective SMG6 inhibition as a promising strategy to enhance tumour immunogenicity and suggests that targeting terminal NMD activity could represent a conceptually distinct avenue for cancer immunotherapy.

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Arpa, E. S., Ricci, V., Shapiro, I. E., Jokic, M., Gonzalez Menendez, I., Quintanilla-Fend, L., Benechet, A. P., Rehwinkel, J., Luther, S. A., Bassani-Sternberg, M., Gatfield, D.. 2025-01-15. Double-stranded RNA responses, neoantigen presentation and suppression of hepatocellular carcinoma through NMD inhibition via endonuclease SMG6. https://doi.org/10.1101/2025.01.13.632668

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