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FAM/USP9x, a Deubiquitinating Enzyme Essential for TGFβ Signaling, Controls Smad4 Monoubiquitination
Sirio Dupont1,Anant Mamidi1,Michelangelo Cordenonsi1,Marco Montagner1,Luca Zacchigna1,Maddalena Adorno1,Graziano Martello1,Michael J. Stinchfield2,Sandra Soligo1,Leonardo Morsut1,Masafumi Inui1,Stefano Moro4,Nicola Modena3,Francesco Argenton3,Stuart J. Newfeld2andStefano Piccolo1,,
1 Department of Histology, Microbiology, and Medical Biotechnologies, University of Padua School of Medicine, viale Colombo 3, 35131 Padua, Italy
2 School of Life Sciences, Arizona State University, Tempe, AZ 85287-4501, USA
3 Department of Biology, University of Padua, via Bassi 58/B, 35131 Padua, Italy
4 Molecular Modeling Section, Department of Pharmaceutical Sciences, University of Padua, via Marzolo 5, 35131 Padua, Italy
Summary
The assembly of the Smad complex is critical for TGFβ signaling, yet the mechanisms that inactivate or empower nuclear Smad complexes are less understood. By means of siRNA screen we identified FAM (USP9x), a deubiquitinase acting as essential and evolutionarily conserved component in TGFβ and bone morphogenetic protein signaling. Smad4 is monoubiquitinated in lysine 519 invivo, a modification that inhibits Smad4 by impeding association with phospho-Smad2. FAM reverts this negative modification, re-empowering Smad4 function. FAM opposes the activity of Ectodermin/Tif1 (Ecto), a nuclear factor for which we now clarify a prominent role as Smad4 monoubiquitin ligase. Our study points to Smad4 monoubiquitination and deubiquitination as a way for cells to set their TGFβ responsiveness: loss of FAM disables Smad4-dependent responses in several model systems, with Ecto being epistatic to FAM. This defines a regulative ubiquitination step controlling Smads that is parallel to those impinging on R-Smad phosphorylation.
