Figure 6.

AMPK signaling failure and unopposed mTORC1 activation in RA T cells. In healthy T cells, AMPK senses the cell’s energy state by trafficking to the lysosomal surface, where it is anchored in the lysosomal membrane through a myristoylated tail. AMPK interacts with the Ragulator-Rag complex, resulting in dissociation and inactivation of mTORC1. In RA T cells, a defect in protein myristoylation leads to mistrafficking and cytosolic retention of AMPK. mTORC1 is retained at the lysosomal surface, where Rheb-GDP converts into Rheb-GTP and switches on the kinase activity of mTORC1. mTORC1 activation persists in RA T cells despite low ATP availability.