2. Academic Validation
  3. TMEM173 Alternative Spliced Isoforms Modulate Viral Replication through the STING Pathway

TMEM173 Alternative Spliced Isoforms Modulate Viral Replication through the STING Pathway

  • Immunohorizons. 2018 Dec 11;2(11):363-376. doi: 10.4049/immunohorizons.1800068.
Estefanía Rodríguez-García 1 2,  Cristina Olagüe 1 2,  Sergio Ríus-Rocabert 3 4,  Roberto Ferrero 1 2,  Carlos Llorens 5,  Esther Larrea 2,  Puri Fortes 1 2,  Jesús Prieto 1 2,  Gloria González-Aseguinolaza 6 2,  Estanislao Nistal-Villan 7 4
Affiliations

Affiliations

  • 1 Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, University of Navarra, Navarra Institute for Health Research, 31008 Pamplona, Spain.
  • 2 Instituto de Salud Tropical, University of Navarra, Navarra Institute for Health Research, 31008 Pamplona, Spain.
  • 3 Microbiology Section, Department of Pharmaceutical and Health Science, Faculty of Pharmacy, University San Pablo-CEU, CEU Universities, Campus Montepríncipe, 28668 Madrid, Spain.
  • 4 Institute of Applied Molecular Medicine, University San Pablo-CEU, CEU Universities, Campus Montepríncipe, 28668 Madrid, Spain; and.
  • 5 Biotechvana, 46980 Valencia, Spain.
  • 6 Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research, University of Navarra, Navarra Institute for Health Research, 31008 Pamplona, Spain; [email protected] [email protected].
  • 7 Microbiology Section, Department of Pharmaceutical and Health Science, Faculty of Pharmacy, University San Pablo-CEU, CEU Universities, Campus Montepríncipe, 28668 Madrid, Spain; [email protected] [email protected].
PMID: 31026807 DOI: 10.4049/immunohorizons.1800068
Abstract

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 t 1/2 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.

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