image: RSV particles enter the cell through membrane fusion or endocytosis by interacting with host receptors. Following entry, the release and uncoating of the incoming genomic RNA subject it to RNA replication, transcription, and translation with the help of structural proteins. The induction of MMP-9 expression is mediated through NF-κB or AP-1 signaling pathways. MMP-9 cleaves TGM2 and enhances PDI activity, which leads to RSV fusion protein transport to the host cell surface and promotes RSV fusion protein-mediated syncytia formation. This process can be inhibited by JNJ0966, a selective inhibitor of MMP-9, or doxycycline hyclate, a broad-spectrum MMP inhibitor.
Credit: HIGHER EDUCATON PRESS
Respiratory syncytial virus (RSV) exploits host proteases to enhance its replication efficiency; however, the precise mechanisms remain unclear. Through high-throughput screening, we identified four matrix metalloproteinase 9 (MMP-9) inhibitors (including JNJ0966 and doxycycline hyclate) that suppress RSV infection in vitro and in vivo. Mechanistic studies revealed a proteolytic cascade wherein MMP-9 cleaves transglutaminase 2 (TGM2) at the PVP375↓VR site, generating an N-terminal fragment (1-375) that activates its protein disulfide isomerase (PDI) activity. This TGM2-dependent PDI activity catalyzes disulfide bond rearrangement in the RSV fusion glycoprotein (F), enabling F protein maturation, a prerequisite for membrane fusion and syncytium formation—key processes driving late-stage viral propagation. Genetic ablation of MMP-9 significantly attenuated RSV infectivity, while pharmacological inhibition reduced pulmonary viral loads and mitigated lung pathology in infected mice. Our study defines a unified MMP-9→TGM2→F axis as the core mechanism driving RSV replication and validates MMP-9 as a therapeutic target.
Key findings from the study include:
- MMP-9 inhibitors show therapeutic efficacy against RSV in vitro/vivo.
- MMP-9 is essential for late-stage RSV replication; MMP-9-/- mouse model reduced infectivity.
- MMP-9 drives pathogenesis by enhancing RSV F-mediated syncytium formation.
- MMP-9 proteolysis of TGM2 enhances PDI activity to drive RSV-mediated syncytium formation.
Journal
Protein & Cell
Method of Research
Experimental study
Subject of Research
Not applicable
Article Title
MMP-9 regulates disulphide isomerase activity of TGM2 to enhance fusion glycoprotein-mediated syncytium formation of respiratory syncytial virus