tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2025 Dec 2;122(48):e2503436122.
doi: 10.1073/pnas.2503436122. Epub 2025 Nov 25. Human coronavirus 3CL protease manipulates host protein STIM1 to facilitate immune evasion
Yoon Young Lee[SUP] #[/SUP][SUP] 1 [/SUP], Ah Reum Lee[SUP] #[/SUP][SUP] 2 [/SUP], Seongkyung Seo[SUP] #[/SUP][SUP] 2 [/SUP], Uni Park[SUP] 3 4 [/SUP], Taehun Kim[SUP] 3 4 [/SUP], Sang Kwon Lee[SUP] 1 [/SUP], Hyeongsun Jeong[SUP] 2 [/SUP], Su Ji Jeong[SUP] 2 [/SUP], Yeong Cheon Kweon[SUP] 2 [/SUP], Go Eun Park[SUP] 1 [/SUP], Min Ji Kim[SUP] 1 [/SUP], Byung-Gyu Kim[SUP] 5 [/SUP], Taejoon Kwon[SUP] 2 [/SUP], Nam-Hyuk Cho[SUP] 3 4 6 7 [/SUP], Hyug Moo Kwon[SUP] 1 [/SUP], Kyungjae Myung[SUP] 2 5 [/SUP], Sang Min Lee[SUP] 1 [/SUP], Chan Young Park[SUP] 2 [/SUP]
Affiliations
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.
Keywords: 3CL protease; IFN-β; STIM1; coronavirus.
. 2025 Dec 2;122(48):e2503436122.
doi: 10.1073/pnas.2503436122. Epub 2025 Nov 25. Human coronavirus 3CL protease manipulates host protein STIM1 to facilitate immune evasion
Yoon Young Lee[SUP] #[/SUP][SUP] 1 [/SUP], Ah Reum Lee[SUP] #[/SUP][SUP] 2 [/SUP], Seongkyung Seo[SUP] #[/SUP][SUP] 2 [/SUP], Uni Park[SUP] 3 4 [/SUP], Taehun Kim[SUP] 3 4 [/SUP], Sang Kwon Lee[SUP] 1 [/SUP], Hyeongsun Jeong[SUP] 2 [/SUP], Su Ji Jeong[SUP] 2 [/SUP], Yeong Cheon Kweon[SUP] 2 [/SUP], Go Eun Park[SUP] 1 [/SUP], Min Ji Kim[SUP] 1 [/SUP], Byung-Gyu Kim[SUP] 5 [/SUP], Taejoon Kwon[SUP] 2 [/SUP], Nam-Hyuk Cho[SUP] 3 4 6 7 [/SUP], Hyug Moo Kwon[SUP] 1 [/SUP], Kyungjae Myung[SUP] 2 5 [/SUP], Sang Min Lee[SUP] 1 [/SUP], Chan Young Park[SUP] 2 [/SUP]
Affiliations
- PMID: 41289387
- DOI: 10.1073/pnas.2503436122
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.
Keywords: 3CL protease; IFN-β; STIM1; coronavirus.