Gimap5 promoted RSV degradation through interaction with M6PR

Abstract Respiratory syncytial virus (RSV) is one of the main pathogens of viral pneumonia and bronchiolitis in infants and young children and life‐threatening diseases among infants and young children. GTPases of the immune‐associated protein family (GIMAP) are new family members of immune‐associated GTPases. In recent years, much attention has been paid to the function of the GIMAP family in coping with infection and stress. Gimap5 is a member of the GIMAP family, which may be correlated with anti‐infectious immunity. RT‐qPCR, Western blot, and indirect immunofluorescence (IFA) were used to detect the expression of Gimap5, M6PR and IGF1R(the major RSV receptor). Transmission electron microscopy (TEM) was used to detect the degradation of RSV in Gimap5‐overexpressed or ‐silent cell lines. Computer virtual screening was used to screen small molecule compounds targeting Gimap5 and the anti‐RSV effects were explored through in vivo and in vitro experiments. GIMAP5 and M6PR were significantly downregulated after RSV infection. Gimap5 accelerated RSV degradation in lysosomes by interacting with M6PR, and further prevented RSV invasion by downregulating the expression of RSV surface receptor IGF1R. Three small molecule compounds targeting Gimap5 were confirmed to be the agonists of Gimap5. The three compounds effectively inhibited RSV infection and RSV‐induced complications. Gimap5 promotes the degradation of RSV and its receptor through interacting with M6PR. Gimap5 agonists can effectively reduce RSV infection and RSV‐induced complication in vivo and in vitro, which provides a new choice for the treatment of RSV.