DHX15 is required to control RNA virus-induced intestinal inflammation

Cell Rep. 2021 Jun 22;35(12):109205. doi: 10.1016/j.celrep.2021.109205.

Abstract

RNA helicases play critical roles in various biological processes, including serving as viral RNA sensors in innate immunity. Here, we find that RNA helicase DEAH-box helicase 15 (DHX15) is essential for type I interferon (IFN-I, IFN-β), type III IFN (IFN-λ3), and inflammasome-derived cytokine IL-18 production by intestinal epithelial cells (IECs) in response to poly I:C and RNA viruses with preference of enteric RNA viruses, but not DNA virus. Importantly, we generate IEC-specific Dhx15-knockout mice and demonstrate that DHX15 is required for controlling intestinal inflammation induced by enteric RNA virus rotavirus in suckling mice and reovirus in adult mice in vivo, which owes to impaired IFN-β, IFN-λ3, and IL-18 production in IECs from Dhx15-deficient mice. Mechanistically, DHX15 interacts with NLRP6 to trigger NLRP6 inflammasome assembly and activation for inducing IL-18 secretion in IECs. Collectively, our report reveals critical roles for DHX15 in sensing enteric RNA viruses in IECs and controlling intestinal inflammation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • HT29 Cells
  • Humans
  • Inflammasomes / metabolism
  • Inflammation / pathology*
  • Inflammation / virology*
  • Interferons / metabolism
  • Interleukin-18 / biosynthesis
  • Intestines / pathology*
  • Intestines / virology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Poly I-C / pharmacology
  • RNA Helicases / metabolism*
  • RNA Viruses / physiology*
  • Receptors, Cell Surface / metabolism

Substances

  • Inflammasomes
  • Interleukin-18
  • Nod-like receptor pyrin domain-containing protein 6, mouse
  • Receptors, Cell Surface
  • Interferons
  • DHX15 protein, human
  • Dhx15 protein, mouse
  • RNA Helicases
  • Poly I-C