TMEM173 Alternative Spliced Isoforms Modulate Viral Replication through the STING Pathway

• Published in: ImmunoHorizons 2018-12, Vol.2 (11), p.363-376
• Main Authors: Rodríguez-García, Estefanía, Olagüe, Cristina, Ríus-Rocabert, Sergio, Ferrero, Roberto, Llorens, Carlos, Larrea, Esther, Fortes, Puri, Prieto, Jesús, González-Aseguinolaza, Gloria, Nistal-Villan, Estanislao
• Format: Article
• Language: English
• Subjects: Alternative Splicing - immunology; Animals; Chlorocebus aethiops; Computer Simulation; HEK293 Cells; HeLa Cells; Herpesvirus 1, Human - genetics; Herpesvirus 1, Human - immunology; Humans; Immunity, Innate; Interferon-beta - immunology; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Membrane Proteins - immunology; Monocytes - immunology; Protein Isoforms; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Vero Cells; Vesicular stomatitis Indiana virus - genetics; Vesicular stomatitis Indiana virus - immunology; Vesicular stomatitis Indiana virus - physiology; Virus Diseases - genetics; Virus Diseases - immunology; Virus Replication - genetics; Virus Replication - immunology
• ISSN: 2573-7732; 2573-7732
• DOI: 10.4049/immunohorizons.1800068

The innate immune system provides a primary line of defense against pathogens. Stimulator of IFN genes (STING), encoded by the TMEM173 gene, is a critical protein involved in IFN-β induction in response to infection by different pathogens. In this study, we describe the expression of three different alternative-spliced human (h) TMEM173 mRNAs producing STING truncated isoforms 1, 2, and 3 in addition to the full-length wild-type (wt) hSTING. All of the truncated isoforms lack exon 7 and share the N-terminal transmembrane region with wt hSTING. Overexpression of the three STING truncated isoforms failed to induce IFN-β, and they acted as selective pathway inhibitors of wt hSTING even in combination with upstream inducer cyclic-di-GMP-AMP synthase. Truncated isoforms alter the stability of wt hSTING, reducing protein to some extent by the induction of proteasome-dependent degradation. Knocking down expression of truncated isoforms increased production of IFN-β by THP1 monocytes in response to intracellular cytosolic DNA or HSV-1 infection. At early stages of infection, viruses like HSV-1 or vesicular stomatitis virus reduced the ratio of full-length wt hSTING/truncated STING isoforms, suggesting the skewing of alternative splicing of STING toward truncated forms as a tactic to evade antiviral responses. Finally, in silico analysis revealed that the human intron-exon gene architecture of TMEM173 (splice sites included) is preserved in other mammal species, predominantly primates, stressing the relevance of alternative splicing in regulating STING antiviral biology.