Cinque, L.L.CinqueLeonibus, C. De.C. De.LeonibusIavazzo, M.M.IavazzoKrahmer, N.N.KrahmerIntartaglia, D.D.IntartagliaSalierno, F.G.F.G.SaliernoCegli, R. DeR. DeCegliMalta, C. DiC. DiMaltaSvelto, M.M.SveltoLanzara, C.C.LanzaraMaddaluno, M.M.MaddalunoWanderlingh, L.G.L.G.WanderlinghHuebner, A.K.A.K.HuebnerCesana, M.M.CesanaBonn, F.F.BonnPolishchuk, E.E.PolishchukHübner, C.A.C.A.HübnerConte, I.I.ConteDikic, I.I.DikicMann, M.M.MannBallabio, A.A.BallabioSacco, F.F.SaccoGrumati, P.P.GrumatiSettembre, C.C.Settembre2022-03-062022-03-062020https://publica.fraunhofer.de/handle/publica/26700210.15252/embj.2020105696Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification of ER-phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER-phagy in response to cellular needs are still largely unknown. We found that the nutrient responsive transcription factors TFEB and TFE3-master regulators of lysosomal biogenesis and autophagy-control ER-phagy by inducing the expression of the ER-phagy receptor FAM134B. The TFEB/TFE3-FAM134B axis promotes ER-phagy activation upon prolonged starvation. In addition, this pathway is activated in chondrocytes by FGF signaling, a critical regulator of skeletal growth. FGF signaling induces JNK-dependent proteasomal degradation of the insulin receptor substrate 1 (IRS1), which in turn inhibits the PI3K-PKB/Akt-mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and enhances FAM134B transcription. Notably, FAM134B is required for protein secretion in chondrocytes, and cartilage growth and bone mineralization in medaka fish. This study identifies a new signaling pathway that allows ER-phagy to respond to both metabolic and developmental cues.en540571572journal article