Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Membrane (M) Protein Inhibits Type I and III Interferon Production by Targeting RIG-I/MDA-5 Signaling
cell biology immunology/immunity inflammation molecular biology
Authors:Yi Zheng et al.
Tags: Cell Biology, Immunology/Immunity, Inflammation, Molecular biology
Expression of the SARS-CoV-2 M protein in HEK293T cells inhibits type I and III IFN induction
SARS-CoV-2 M inhibits formation of a signalling complex containing RIG-I and MAVS, and binds TBK1
Expression of SARS-CoV-2 M in HEK293T cells reduces IRF3 nuclear translocation in response to VSV infection
This study shows that expression of the M protein from SARS-CoV-2 in HEK293T cells inhibits type I and III IFN induction in response to immunostimulatory RNA. The authors propose this is due to the abilities of the M protein, which is localised on Golgi and ER, to block the RIG-I - MAVS interaction as well as to bind TBK1, as indicated by co-immunoprecipitation experiments. Additionally, in HEK293T expressing the M protein and infected with the RNA virus SeV, phosphorylation and translocation of IRF3 to the nucleus are inhibited, consistent with lack of type I and III IFN responses. These cells are also more permissive for replication of the model virus VSV-GFP.
Impact for SARS-CoV2/COVID19 research efforts
Understand the immune response to SARS-CoV2/COVID19
Understand the virology and/or cell biology of SARS-CoV2/COVID19
This study suggests that the defective IFN response to SARS-CoV-2 could be due to the ability of the M protein to block the IRF3 signalling pathway.
In vitro study
Strengths and limitations of the paper
Novelty: The study uncovers a role of the viral M protein in the dampening of the type I and III IFN response. The study suggests that this is due to a direct interaction with TBK1 and the RIG-I - MAVS complex. The data are of high technical quality.
Standing in the field: It is known that SARS-CoV-2 infection does not give rise to a potent IFN response:
This study offers an explanation for the observation that the IRF3 pathway is blocked by SARS-CoV-2:
Viral model used:none; overexpression of the M protein from SARS-CoV-2 (not better specified)
Translatability:Remote- the efficacy of IFNs in the in vitro treatment is already well known
The models used by the authors throughout the study are somewhat artificial. The cells used (HEK293T) not a target of SARS-CoV-2, and, as the authors note, none of the in vitro infection is with SARS-CoV-2 (for the lack of cat 3 labs). Other RNA viruses are used but this limits the conclusions that can be drawn.
The authors show colocalisation of the M protein in Figure 3 but there is no quantification or statistical analysis.
The co-immunoprecipitations of the M protein with RIG-I, MDA-5, MAVS, TBK1 and IRF3 are done by using overexpressed tagged M protein only. In future experiments, it would have been nice to test IP of endogenous M from infected cells.
It would have been interesting to see how mutating the M protein affects the binding to innate signalling proteins, and which domains are key to block IRF3 nuclear translocation.