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

ABSTRACT 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.