Loss of RIG-I leads to a functional replacement with MDA5 in the Chinese tree shrew
1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan 650223, China;
Abstract:
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.
Insights
RIG-I-like receptors (RLRs) are crucial for detecting viruses. In tree shrews, RIG-I was lost, but MDA5 and LGP2 evolved to compensate, maintaining antiviral defense.
Area of Science:
- Immunology
- Evolutionary Biology
- Virology
Background:
- RIG-I-like receptors (RLRs) are essential cytoplasmic sensors for viral pathogen-associated molecular patterns (PAMPs).
- RLRs, including RIG-I, MDA5, and LGP2, play a critical role in innate antiviral immunity.
- The evolution of these sensors reflects adaptation to diverse pathogenic challenges.
Purpose of the Study:
- To investigate the evolutionary trajectory of RLRs in the Chinese tree shrew lineage.
- To understand the functional adaptation of MDA5 and LGP2 following the loss of RIG-I.
- To elucidate the molecular mechanisms underlying compensatory antiviral responses in tree shrews.
Main Methods:
- Comparative genomics and evolutionary analysis to identify RLR gene loss and selection pressures.
- Functional assays (e.g., type I IFN induction) to assess viral sensing capabilities of tree shrew MDA5 (tMDA5) and LGP2 (tLGP2).
- Co-immunoprecipitation assays to study protein-protein interactions between tMDA5 and adaptor proteins like tMITA.
Main Results:
- Evidence of RIG-I gene loss in the Chinese tree shrew lineage.
- Significant positive selection identified in tMDA5 and tLGP2 genes in tree shrews.
- tMDA5 and tMDA5/tLGP2 complexes demonstrated the ability to sense Sendai virus and induce type I interferon (IFN) production.
- tMDA5 was found to interact with the adaptor tMITA, a function previously associated only with RIG-I.
Conclusions:
- The loss of RIG-I in tree shrews was compensated by the functional adaptation of MDA5 and LGP2.
- Positively selected sites in tMDA5 likely conferred the ability to sense RNA viruses and interact with downstream signaling molecules, replacing RIG-I's function.
- These findings highlight the dynamic evolution and functional plasticity of innate antiviral immunity in vertebrates.
