NUDT21 Links Mitochondrial IPS-1 to RLR-Containing Stress Granules and Activates Host Antiviral Defense

J Immunol. 2021 Jan 1;206(1):154-163. doi: 10.4049/jimmunol.2000306. Epub 2020 Nov 20.


Viral RNA in the cytoplasm of mammalian host cells is recognized by retinoic acid-inducible protein-I-like receptors (RLRs), which localize to cytoplasmic stress granules (SGs). Activated RLRs associate with the mitochondrial adaptor protein IPS-1, which activates antiviral host defense mechanisms, including type I IFN induction. It has remained unclear, however, how RLRs in SGs and IPS-1 in the mitochondrial outer membrane associate physically and engage in information transfer. In this study, we show that NUDT21, an RNA-binding protein that regulates alternative transcript polyadenylation, physically associates with IPS-1 and mediates its localization to SGs in response to transfection with polyinosinic-polycytidylic acid [poly(I:C)], a mimic of viral dsRNA. We found that despite its well-established function in the nucleus, a fraction of NUDT21 localizes to mitochondria in resting cells and becomes localized to SGs in response to poly(I:C) transfection. NUDT21 was also found to be required for efficient type I IFN induction in response to viral infection in both human HeLa cells and mouse macrophage cell line RAW264.7 cells. Our results together indicate that NUDT21 links RLRs in SGs to mitochondrial IPS-1 and thereby activates host defense responses to viral infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cardiovirus Infections / metabolism*
  • Cleavage And Polyadenylation Specificity Factor / genetics
  • Cleavage And Polyadenylation Specificity Factor / metabolism*
  • DEAD Box Protein 58 / metabolism*
  • Encephalomyocarditis virus / physiology*
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Interferon Type I / genetics
  • Interferon Type I / metabolism
  • Mice
  • Mitochondria / metabolism*
  • Newcastle Disease / metabolism*
  • Newcastle disease virus / physiology*
  • Poly I-C / immunology
  • Protein Transport
  • RAW 264.7 Cells
  • RNA, Small Interfering / genetics
  • RNA, Viral / immunology
  • Receptors, Immunologic / metabolism*
  • Secretory Vesicles / metabolism*
  • Stress, Physiological


  • Adaptor Proteins, Signal Transducing
  • Cleavage And Polyadenylation Specificity Factor
  • Interferon Type I
  • MAVS protein, human
  • Nudt21 protein, human
  • RNA, Small Interfering
  • RNA, Viral
  • Receptors, Immunologic
  • DDX58 protein, human
  • DEAD Box Protein 58
  • Poly I-C