mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation in tuberous sclerosis complex

Monika Pema, Luca Drusian, Marco Chiaravalli, Maddalena Castelli, Qin Yao, Sara Ricciardi, Stefan Somlo, Feng Qian, Stefano Biffo and Alessandra Boletta ()
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Monika Pema: Dibit San Raffaele Scientific Institute
Luca Drusian: Dibit San Raffaele Scientific Institute
Marco Chiaravalli: Dibit San Raffaele Scientific Institute
Maddalena Castelli: Dibit San Raffaele Scientific Institute
Qin Yao: University of Maryland School of Medicine
Sara Ricciardi: INGM
Stefan Somlo: Yale University School of Medicine
Feng Qian: University of Maryland School of Medicine
Stefano Biffo: INGM
Alessandra Boletta: Dibit San Raffaele Scientific Institute

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: Abstract Previous studies report a cross-talk between the polycystic kidney disease (PKD) and tuberous sclerosis complex (TSC) genes. mTOR signalling is upregulated in PKD and rapamycin slows cyst expansion, whereas renal inactivation of the Tsc genes causes cysts. Here we identify a new interplay between the PKD and TSC genes, with important implications for the pathophysiology of both diseases. Kidney-specific inactivation of either Pkd1 or Tsc1 using an identical Cre (KspCre) results in aggressive or very mild PKD, respectively. Unexpectedly, we find that mTORC1 negatively regulates the biogenesis of polycystin-1 (PC-1) and trafficking of the PC-1/2 complex to cilia. Genetic interaction studies reveal an important role for PC-1 downregulation by mTORC1 in the cystogenesis of Tsc1 mutants. Our data potentially explain the severe renal manifestations of the TSC/PKD contiguous gene syndrome and open new perspectives for the use of mTOR inhibitors in autosomal dominant PKD caused by hypomorphic or missense PKD1 mutations.

Date: 2016
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DOI: 10.1038/ncomms10786

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