RIG-I like receptor sensing of host RNAs facilitates the cell-intrinsic immune response to KSHV infection

Nat Commun. 2018 Nov 19;9(1):4841. doi: 10.1038/s41467-018-07314-7.

Abstract

The RIG-I like receptors (RLRs) RIG-I and MDA5 are cytosolic RNA helicases best characterized as restriction factors for RNA viruses. However, evidence suggests RLRs participate in innate immune recognition of other pathogens, including DNA viruses. Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus and the etiological agent of Kaposi's sarcoma and primary effusion lymphoma (PEL). Here, we demonstrate that RLRs restrict KSHV lytic reactivation and we demonstrate that restriction is facilitated by the recognition of host-derived RNAs. Misprocessed noncoding RNAs represent an abundant class of RIG-I substrates, and biochemical characterizations reveal that an infection-dependent reduction in the cellular triphosphatase DUSP11 results in an accumulation of select triphosphorylated noncoding RNAs, enabling their recognition by RIG-I. These findings reveal an intricate relationship between RNA processing and innate immunity, and demonstrate that an antiviral innate immune response can be elicited by the sensing of misprocessed cellular RNAs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • DEAD Box Protein 58 / antagonists & inhibitors
  • DEAD Box Protein 58 / genetics*
  • DEAD Box Protein 58 / immunology
  • Dual-Specificity Phosphatases / genetics
  • Dual-Specificity Phosphatases / immunology
  • Gene Expression Profiling
  • HEK293 Cells
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / immunology*
  • Host-Pathogen Interactions*
  • Humans
  • Immunity, Innate
  • Interferon-Induced Helicase, IFIH1 / antagonists & inhibitors
  • Interferon-Induced Helicase, IFIH1 / genetics*
  • Interferon-Induced Helicase, IFIH1 / immunology
  • Lymphocytes / immunology
  • Lymphocytes / virology
  • Nucleic Acid Conformation
  • Phosphorylation
  • RNA Processing, Post-Transcriptional*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • RNA, Untranslated / genetics*
  • RNA, Untranslated / immunology
  • Signal Transduction
  • Virus Activation

Substances

  • RNA, Small Interfering
  • RNA, Untranslated
  • DUSP11 protein, human
  • Dual-Specificity Phosphatases
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • Interferon-Induced Helicase, IFIH1