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Assays for the Specific Growth Rate and Cell-binding Ability of Rotavirus
Published on: January 28, 2019
CLDN3 inhibits rotavirus attachment by targeting residue 74 of VP7
Yudi Pan1, Jiapei Huang2, Longjun Guo1
1State Key Laboratory of Animal Disease Control and Prevention, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China.
Abstract:
Rotavirus (RV) VP8* peptide-induced CLDN3 mislocalization supports the hypothesis that CLDN3 negatively regulates viral binding, while the molecular basis of this inhibitory function remains unresolved. To counteract the CLDN3 defense strategies, RV infection indeed disrupts its localization to the plasma membrane. We also found that RV infection could reduce its protein levels in both in vitro and animal models. Knockdown or knockout of CLDN3 effectively promotes RV binding and entry. Further, we found that CLDN3 EC1 loop could interact with the N-terminal domain of VP7 and structural studies reveal a conserved glutamic acid at position 74 (E74) in VP7 as critical for the CLDN3-VP7 interaction. Mechanistically, VP7 is involved in viral attachment. Binding of the CLDN3 EC1 loop to VP7 reduces viral adsorption, whereas the E74K mutation disrupts the CLDN3-VP7 interaction and consequently enhances viral attachment. More importantly, a single E74K mutation enhances viral pathogenicity in vivo, confirming this interaction's biological significance. Our results demonstrate for the first time that the tight junction protein CLDN3 acts as a decoy receptor that specifically counters the VP7-mediated viral attachment. This highlights the antiviral mechanisms utilized by CLDN3.
Insights
Rotavirus (RV) uses VP7 to attach to cells, but the tight junction protein CLDN3 blocks this. CLDN3 acts as a decoy receptor, preventing RV binding and infection.
Area of Science:
- Virology
- Cell Biology
- Structural Biology
Background:
- Rotavirus (RV) binding and entry mechanisms are crucial for infection.
- Claudin-3 (CLDN3) is implicated in negatively regulating RV binding, but its precise role and molecular basis are unclear.
- Understanding host-pathogen interactions is key to developing antiviral strategies.
Purpose of the Study:
- To elucidate the molecular mechanism by which CLDN3 inhibits Rotavirus (RV) attachment.
- To identify the specific viral protein and interaction site involved in CLDN3-mediated antiviral activity.
- To investigate the biological significance of the CLDN3-RV interaction in viral pathogenicity.
Main Methods:
- Investigated CLDN3 localization and protein levels upon RV infection in vitro and in vivo.
- Utilized knockdown and knockout models to assess the effect of CLDN3 on RV binding and entry.
- Performed co-immunoprecipitation and structural studies to identify the interaction between CLDN3 and RV VP7 protein.
- Analyzed the impact of specific mutations (E74K) in VP7 on CLDN3 interaction and viral attachment/pathogenicity.
Main Results:
- RV infection disrupts CLDN3 localization and reduces its protein levels, promoting viral entry.
- CLDN3's extracellular loop 1 (EC1) interacts with the N-terminal domain of RV VP7.
- A conserved glutamic acid at position 74 (E74) in VP7 is critical for the CLDN3-VP7 interaction.
- Disruption of this interaction via E74K mutation enhances viral attachment and pathogenicity in vivo.
- CLDN3 acts as a decoy receptor, specifically inhibiting VP7-mediated viral attachment.
Conclusions:
- CLDN3 functions as a decoy receptor that specifically antagonizes Rotavirus (RV) VP7-mediated attachment.
- The interaction between CLDN3 EC1 and VP7 E74 is a critical antiviral mechanism.
- Targeting this interaction could offer novel therapeutic strategies against Rotavirus infections.
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