This technology demonstrates for the first time the interaction of Rheb and Rag GTPases to regulate mTORC1. Both GTPases are upregulated in a double knockout mouse model resulting in severe liver disease. This model shows synergistic interaction of these proteins and can be a useful model in studying liver disease.
· mTORC1 activation studies
· Characterization and treatment of severe liver disease
· Possible use in chemical screening for molecules to treat liver disease
mTOR complex 1 (mTORC1) is a protein kinase important for liver metabolism. Two small GTPases, Rheb and Rag regulate mTORC1. Although the interactions of Rheb and Rag with mTORC1 have been studied extensively, interaction between the two GTPases had not been studied until recently.
This technology consists of a mouse model in which both Rheb and Rag are upregulated. Simultaneous upregulation of both enzymes leads to severe liver disease, consistent with human livers affected by severe hepatitis. This phenotype is much more severe than is seen by upregulation of either enzyme alone. Thus, this mouse model provides a means to study severe liver disease and unregulated mTORC1 activation.
Figure 1 – Knockout of either Tsc1 or Depdc5 results in increased expression of Rheb or Rag respectively and results in liver disease. Double knockout results in synergistically increased severity of disease as noted by increased necrosis and fibrosis. Figure published: https://www.nature.com/articles/s41421-019-0131-9