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Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods
Published on: December 21, 2019
Human coronavirus 3CL protease manipulates host protein STIM1 to facilitate immune evasion
Yoon Young Lee1, Ah Reum Lee2, Seongkyung Seo2
1Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea.
Abstract:
Coronaviruses rely on intricate interactions with host proteins to create an environment conducive to their replication and survival. The 3CL protease of coronavirus acts as a key mediator, serving a dual role in cleaving viral polyproteins to produce essential components for replication and targeting host proteins to disrupt regulatory pathways and suppress immune defenses. However, the mechanisms by which 3CL protease manipulates host proteins remain poorly understood. Here, we identify STIM1, a substrate of the 3CL protease, as a dual immune suppressor. Cleavage at the Q496 residue generates two stable products, N-terminal (NT) and C-terminal (CT) fragments, which acquire de novo immunomodulatory functions. NT suppresses MAVS aggregation and MAVS-TRAF2-TBK1 signalosome formation, while CT attenuates IKKα-induced p65 phosphorylation and nuclear translocation by interacting with HSP70. Collectively, these dual modules simultaneously lead to the suppression of IFN-β production and the weakening of antiviral defenses. These findings reveal a distinct function of STIM1 and delineate a strategy employed by coronaviruses to modulate host immunity, offering insights into viral pathogenesis and potential avenues for therapeutic intervention.
Insights
Coronaviruses use 3CL protease to cleave STIM1, a protein that suppresses the immune system. This cleavage generates fragments that weaken antiviral defenses, aiding viral survival.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- Coronaviruses utilize host proteins for replication and immune evasion.
- The 3CL protease is crucial for viral replication and host immune modulation.
- Mechanisms of 3CL protease manipulation of host proteins are not fully understood.
Purpose of the Study:
- To identify host protein substrates of the 3CL protease.
- To elucidate the role of STIM1 (stromal interaction molecule 1) as a target of 3CL protease.
- To understand how STIM1 cleavage impacts host antiviral responses.
Main Methods:
- Proteolytic cleavage assays to identify STIM1 as a substrate.
- Analysis of STIM1 N-terminal (NT) and C-terminal (CT) fragments.
- Investigation of NT's effect on MAVS aggregation and signalosome formation.
- Assessment of CT's interaction with HSP70 and effect on p65 phosphorylation.
Main Results:
- STIM1 is cleaved by 3CL protease at Q496 into stable NT and CT fragments.
- NT suppresses MAVS aggregation and MAVS-TRAF2-TBK1 signalosome assembly.
- CT inhibits IKKα-induced p65 phosphorylation and nuclear translocation via HSP70 interaction.
- Combined action of NT and CT significantly reduces IFN-β production and antiviral defense.
Conclusions:
- STIM1 acts as a dual immune suppressor upon cleavage by coronavirus 3CL protease.
- Cleaved STIM1 fragments exhibit novel immunomodulatory functions.
- Coronaviruses employ STIM1 cleavage as a strategy to suppress host immunity and enhance viral pathogenesis.
