FAM134C Blocks TGF-β Signaling By Degrading TβRⅠ Through Autophagy

The Transforming Growth Factor-β(TGF-β)superfamily comprises 33 members in human,including TGF-β,Activins,Nodals,bone morphogenetic proteins(BMPs),and growth and differentiation factors(GDFs),participating in the regulation of vital biological roles such as embryonic development and tissue homeostasis.Misregulation of TGF-β signaling is associated with many diseases,including tumor development and orgnic fibrosis.The classical TGF-β signaling starts with TGF-β ligand binding to typeⅠ and type Ⅱ receptors(TβRⅠ and TβRⅡ),followed by TβRⅠ-mediated phosphorylation and activation of R-Smads.Then,the Smad complex,formed by R-Smad and Co-Smad,transfroms into nucleus and binds to gene promoters,inducing or repressing target gene transcription.TβRⅠ plays a central role in transducing extracellular TGF-β signal to activate intercellular both Smad-dependent and-independent signaling pathways.To search new regulatory factors in TGF-β signaling,we have found Family with Sequence Similarity 134,Member C(FAM134C)that interacts with TβRⅠ.Further experiments showed that FAM134C decreased the protein level of TβRⅠ through autophagy.Accordingly,autophagy inhibitors blocked the degradation of TβRⅠ.Furthermore,the ability of FAM134C to mediate TβRⅠ degradation depended on its LC3-interacting domain(LIR),as the mutation of LIR also blocked TβRⅠ degradation.Functionally,overexpression of FAM134C attenuated the TGF-β-induced phosphorylation of Smad2/3 and transcriptional responses.FAM 134C suppressed TGFβ-induced cell cycle arrest and fibrosis related gene expression.Downregulation of FAM134C accelerated the ability of TGF-β-induced migration and invasion of cancer cells.Moreover,we have generated FAM134C knockout(KO)mice.Compared with wildtype mice,FAM134C KO mice exhibited accelerated renal fibrosis induced by unilateral ureteral occlusion(UUO),which could be alleviated by TβRⅠ inhibitor SB525334.Overall,we have found FAM134C negatively regulates TGF-β signaling through inducing autophagy-dependent degradation of TβRⅠ.Our research may elucidate a new molecular mechanism underlying regulation of TβRI availability in physiological processes and provide a new foundation for therapies of diseases related with TGF-βdysregulation.