Altered cellular proteostasis, including conditions such as endoplasmic reticulum (ER) stress, may contribute to the pathogenesis of renal angiomyolipomas and cysts in tuberous sclerosis complex (TSC). ER stress describes accumulation of misfolded proteins in the ER lumen, to which the cell responds by initiating an adaptive mechanism, the unfolded protein response (UPR), to counteract the imbalance or initiate apoptosis if ER stress is prolonged. In TSC, mutations in
deregulate activity of the mammalian target of rapamycin complex 1 (mTORC1), which results in constitutive protein translation. Our laboratory recently found that
human renal angiomyolipoma cells experience elevated ER stress, and are more sensitive to treatments that exacerbate ER stress, than
-sufficient counterparts. We also determined that ER stress is elevated in human TSC patient-derived renal angiomyolipoma and cyst tissue. The goal of this project is to determine whether altered proteostasis, such as ER stress, can be leveraged therapeutically for treatment of TSC renal disease.
Tuberous Sclerosis Alliance
Collaborators: Julie Yin, MD, Children's Hospital of Atlanta
Enhanced sensitivity of human renal angiomyolipoma cells to ER stress. Human renal angiomyolipoma cells carrying a mutation in TSC2 (TRI102, panels "A" and "C") are more sensitive to induction of endoplasmic reticulum (ER) stress by treatment with the proteasome inhibitor MG-132, as indicated by enhanced nuclear expression of CHOP in panel "C", than cells in which TSC2 has been re-expressed (TRI103, panels "B" and "D"). From Siroky et al. AJP Renal, 2012.