Regulation and function of the cytosolic viral RNA sensor RIG-I in pancreatic beta cells

Biochim Biophys Acta. 2009 Nov;1793(11):1768-75. doi: 10.1016/j.bbamcr.2009.09.005. Epub 2009 Sep 10.


Enteroviral infections are associated with type I diabetes. The mechanisms by which viruses or viral products such as double-stranded RNA (dsRNA) affect pancreatic beta cell function and survival remain unclear. We have shown that extracellular dsRNA induces beta cell death via Toll-like receptor-3 (TLR3) signaling whereas cytosolic dsRNA triggers the production of type I interferons and apoptosis via a TLR3-independent process. We presently examined expression of the intracellular viral RNA sensors, the RNA helicases RIG-I and MDA5, and documented the functionality of RIG-I in pancreatic beta cells. FACS-purified rat beta cells and islet cells from wild-type or TLR3(-/-) mice were cultured with or without the RIG-I-specific ligand 5'-triphosphate single-stranded RNA (5'triP-ssRNA), the synthetic dsRNA polyI:C (PIC) or 5'OH-ssRNA (negative control); the RNA compounds were added in the medium or transfected in the cells using lipofectamine. RIG-I and MDA5 expression were determined by real-time RT-PCR. NF-kappaB and IFN-beta promoter activation were studied in the presence or absence of a dominant-negative form of RIG-I (DN-RIG-I). Both extracellular (PICex) and intracellular (PICin) PIC increased expression of RIG-I and MDA5 in pancreatic beta cells. TLR3 deletion abolished PICex-induced up-regulation of the helicases in beta cells but not in dendritic cells. PICin-induced NF-kappaB and IFN-beta promoter activation were prevented by the DN-RIG-I. The RIG-I-specific ligand 5'triP-ssRNA induced IFN-beta promoter activation and beta cell apoptosis. Our results suggest that the RIG-I pathway is present and active in beta cells and could contribute to the induction of insulitis by viral RNA intermediates.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cytosol / enzymology*
  • Cytosol / virology
  • DEAD-box RNA Helicases / biosynthesis
  • Enterovirus / metabolism*
  • Enterovirus Infections / enzymology*
  • Enterovirus Infections / genetics
  • Gene Deletion
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / genetics
  • Insulin-Secreting Cells / enzymology*
  • Insulin-Secreting Cells / virology
  • Interferon-Induced Helicase, IFIH1
  • Interferon-beta / biosynthesis
  • Male
  • Membrane Proteins / biosynthesis*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / biosynthesis*
  • Poly I-C / pharmacology
  • Promoter Regions, Genetic / genetics
  • RNA, Double-Stranded / metabolism*
  • RNA, Viral / metabolism*
  • Rats
  • Rats, Wistar
  • Receptors, Cell Surface
  • Toll-Like Receptor 3 / genetics
  • Toll-Like Receptor 3 / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / genetics


  • Membrane Proteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • RNA, Double-Stranded
  • RNA, Viral
  • Receptors, Cell Surface
  • Robo3 protein, mouse
  • TLR3 protein, mouse
  • TLR3 protein, rat
  • Toll-Like Receptor 3
  • Interferon-beta
  • Ifih1 protein, mouse
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • Poly I-C