Fig 13. A model on the functional role of the Fis1 mitochondrial fission protein 1 in the formation of virus-induced membrane contact sites.

(A) In the absence of tombusvirus replication, the role of Fis1 in MCS formation is undefined and needs to be investigated. (B) Expression of the abundant p33 replication protein of TBSV leads to p33 molecules-driven efficient recruitment of Fis1 to peroxisome membranes, likely with the assistance of the cellular Pex19 peroxisomal transport protein. P33 also binds to the ER-resident VAP tethering protein and Sac1 PI4P phosphatase and the cytosolic oxysterol-binding proteins (ORP). The cellular PI4K kinase is also recruited into vMCS. All these processes lead to the tethering of the peroxisomal membranes to the syntaxin 18-like Ufe1 and Use1 SNARE proteins-marked subdomains of the ER membrane, resulting in the formation and stabilization of vMCSs. (C) The interplay between the co-opted ORP proteins, PI(4)P phosphoinositide and Sac1 facilitates the enrichment of sterols and other lipids within the peroxisomal membranes. (D) These processes render the peroxisomal membranes highly suitable for the formation of the virus-induced spherules, which harbor the VRCs needed for virus replication. Overall, by hijacking these cellular components for pro-viral functions makes tombusviruses capable of building nuclease and protease-insensitive virus replication compartment. (E) A scheme of the TBSV-infected cell with the formation of vMCS and the replication compartment. Please note the related CIRV builds similar virus-induced structures utilizing the mitochondria, instead of peroxisomes, and the ER membranes.