Coronavirus M Protein Hijacks Toll-Interacting Protein (TOLLIP) to Suppress NF-κB Signaling and Promote Immune Evasion.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) employs sophisticated strategies to subvert host innate immunity, a critical determinant of viral establishment and dissemination. Nevertheless, the immunomodulatory functions of coronavirus structural proteins remain incompletely understood. Here, we identify the evolutionarily conserved membrane (M) protein of SARS-CoV-2 as an innate immune antagonist that suppresses nuclear factor kappa-B (NF-κB) activation. Functional assays revealed that the M protein markedly inhibited NF-κB activation and reduced proinflammatory cytokine production in vitro. In lung epithelial M-expressing mouse, M significantly attenuated LPS-induced inflammation. Mechanistically, M protein from diverse coronaviruses directly interacts with host Toll-interacting protein (TOLLIP), stabilizing TOLLIP‒IRAK1 complex, preventing IRAK1 activation, thereby suppressing downstream NF-κB signaling and creating a permissive cellular microenvironment for viral replication. We mapped a conserved linker region within the M protein as the core motif mediating this interaction. This binding is highly conserved across coronaviruses, highlighting the fundamental role of the M-TOLLIP axis in viral immune evasion. Our findings reveal a conserved pan-coronavirus immune evasion strategy by which coronaviruses target TOLLIP to subvert Toll-like receptor (TLR)-NF-κB signaling. The conserved M-linker region thus represents a potential broad-spectrum antiviral target, providing a structural framework for developing next-generation antivirals against current and emerging coronavirus threats.