# MMP-9 regulates disulphide isomerase activity of TGM2 to enhance fusion glycoprotein-mediated syncytium formation of respiratory syncytial virus

## TL;DR

This study shows how the enzyme MMP-9 helps the RSV virus replicate by activating another enzyme, TGM2, which supports virus spread in the lungs.

## Contribution

The study identifies a novel proteolytic cascade involving MMP-9 and TGM2 that enhances RSV replication and validates MMP-9 as a therapeutic target.

## Key findings

- MMP-9 cleaves TGM2 to activate its PDI activity, which is essential for RSV fusion glycoprotein maturation.
- Pharmacological inhibition of MMP-9 reduces RSV infectivity and lung pathology in mice.
- Genetic removal of MMP-9 significantly attenuates RSV replication.

## Abstract

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.