Human coronavirus 3CL protease manipulates host protein STIM1 to facilitate immune evasion
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Yoon Young Lee
Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Ah Reum Lee
Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Seongkyung Seo
Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Uni Park
Department of Microbiology and Immunology, College of Medicine, Seoul National University
Taehun Kim
Department of Microbiology and Immunology, College of Medicine, Seoul National University
Sang Kwon Lee
Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Hyeongsun Jeong
Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Su Ji Jeong
Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Yeong Cheon Kweon
Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Go Eun Park
Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Min Ji Kim
Byung-Gyu Kim
Center for Genomic Integrity, Institute for Basic Science, Ulsan National Institute of Science and Technology
Taejoon Kwon
Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Nam-Hyuk Cho
Department of Microbiology and Immunology, College of Medicine, Seoul National University
Hyug Moo Kwon
Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Kyungjae Myung
Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Sang Min Lee
Department of Biological Sciences, College of Information and Biotechnology, Ulsan National Institute of Science and Technology
Chan Young Park
Department of Biomedical Engineering, College of Information and Biotechnology, Ulsan National Institute of Science and Technology