TBC1D7 Is a Third Subunit of the TSC1-TSC2 Complex Upstream of mTORC1

SummaryThe tuberous sclerosis complex (TSC) tumor suppressors form the TSC1-TSC2 complex, which limits cell growth in response to poor growth conditions. Through its GTPase-activating protein (GAP) activity toward Rheb, this complex inhibits the mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a key promoter of cell growth. Here, we identify and biochemically characterize TBC1D7 as a stably associated and ubiquitous third core subunit of the TSC1-TSC2 complex. We demonstrate that the TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional complex that senses specific cellular growth conditions and possesses Rheb-GAP activity. Sequencing analyses of samples from TSC patients suggest that TBC1D7 is unlikely to represent TSC3. TBC1D7 knockdown decreases the association of TSC1 and TSC2 leading to decreased Rheb-GAP activity, without effects on the localization of TSC2 to the lysosome. Like the other TSC-TBC components, TBC1D7 knockdown results in increased mTORC1 signaling, delayed induction of autophagy, and enhanced cell growth under poor growth conditions.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (202 K)Download as PowerPoint slideHighlights► TBC1D7 is a ubiquitous, stably associated third core subunit of the TSC1-TSC2 complex ► TSC1 binds to and stabilizes both TSC2 and TBC1D7 within the trimeric complex ► The TSC1-TSC2-TBC1D7 (TSC-TBC) complex is the functional Rheb-GAP upstream of mTORC1 ► As part of the TSC-TBC complex, TBC1D7 inhibits mTORC1 and downstream functions