Loss of RIG-I leads to a functional replacement with MDA5 in the Chinese tree shrew

Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):10950-5. doi: 10.1073/pnas.1604939113. Epub 2016 Sep 12.


The function of the RIG-I-like receptors (RLRs; including RIG-I, MDA5, and LGP2) as key cytoplasmic sensors of viral pathogen-associated molecular patterns (PAMPs) has been subjected to numerous pathogenic challenges and has undergone a dynamic evolution. We found evolutionary evidence that RIG-I was lost in the Chinese tree shrew lineage. Along with the loss of RIG-I, both MDA5 (tMDA5) and LGP2 (tLGP2) have undergone strong positive selection in the tree shrew. tMDA5 or tMDA5/tLGP2 could sense Sendai virus (an RNA virus posed as a RIG-I agonist) for inducing type I IFN, although conventional RIG-I and MDA5 were thought to recognize distinct RNA structures and viruses. tMDA5 interacted with adaptor tMITA (STINGTMEM173/ERIS), which was reported to bind only with RIG-I. The positively selected sites in tMDA5 endowed the substitute function for the lost RIG-I. These findings provided insights into the adaptation and functional diversity of innate antiviral activity in vertebrates.

Keywords: MDA5; RIG-I; functional replacement; positive selection; tree shrew.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line
  • Conserved Sequence
  • DEAD-box RNA Helicases / deficiency*
  • DEAD-box RNA Helicases / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Interferon-Induced Helicase, IFIH1 / chemistry
  • Interferon-Induced Helicase, IFIH1 / metabolism*
  • Kidney / cytology
  • Ligands
  • Membrane Proteins
  • Mutant Proteins / metabolism
  • Phylogeny
  • Protein Binding
  • RNA Viruses / metabolism
  • RNA, Viral / metabolism
  • Selection, Genetic
  • Shrews / genetics
  • Shrews / metabolism*
  • Shrews / virology


  • Ligands
  • Membrane Proteins
  • Mutant Proteins
  • RNA, Viral
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1