TBC1D7 Is a Core Subunit of the TSC1–TSC2 Complex

Tuberous sclerosis is a tumor syndrome caused by mutations in tuberous sclerosis complex 1 (TSC1) and TSC2, which encode proteins that are believed to form a heterodimer and negatively regulate mTOR complex 1 (mTORC1) signaling. It remains unproven whether any TSC1 or TSC2 interacting proteins that have been identified are subunits of the TSC1–TSC2 complex or play a role in mTORC1 regulation. Dibble and colleagues identified Tre2–Bub2–Cdc16 (TBC) 1 domain family member 7 (TBC1D7) as a binding partner of epitope-tagged TSC1 and TSC2. An interaction between TBC1D7 and endogenous TSC1 and TSC2 was also confirmed in a broad spectrum of mouse tissue types and was shown to be highly resistant to salt and detergent. Furthermore, these proteins were interdependent for their association, because TBC1D7 knockdown decreased the interaction between TSC1 and TSC2, and TSC1 was required for full TBC1D7 stability and incorporation into the complex. Taken together, these data establish that TBC1D7 is a stably associated third subunit of the TSC1–TSC2 complex. Like TSC1 and TSC2, TBC1D7 also was required to fully inhibit mTORC1 signaling upon growth factor withdrawal, and knockdown of TBC1D7 in either mouse or human cells led to increased growth factor–independent mTORC1 signaling. Knockdowns of TBC1D7 delayed the initiation of autophagy and led to increased cell size, 2 hallmarks of failed mTORC1 inhibition that similarly occur upon knockdown of TSC1 and TSC2. Although TBC1D7 is not likely to be a third tuberous sclerosis gene, given that no TBC1D7 coding exon mutations were identified among 12 patients with tuberous sclerosis lacking germline TSC1 or TSC2 mutations, these findings provide insight into the function of the TSC1–TSC2 complex and the regulation of mTORC1 signaling.

Dibble CC, Elis W, Menon S, Qin W, Klekota J, Asara JM, et al. TBC1D7 is a third subunit of the TSC1–TSC2 complex upstream of mTORC1. Mol Cell 2012 Jul 12 [Epub ahead of print].