Lysosomal 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.

MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B / Cinque, Laura; De Leonibus, Chiara; Iavazzo, Maria; Krahmer, Natalie; Intartaglia, Daniela; Salierno, Francesco Giuseppe; De Cegli, Rossella; Di Malta, Chiara; Svelto, Maria; Lanzara, Carmela; Maddaluno, Marianna; Wanderlingh, Luca Giorgio; Huebner, Antje K; Cesana, Marcella; Bonn, Florian; Polishchuk, Elena; Hübner, Christian A; Conte, Ivan; Dikic, Ivan; Mann, Matthias; Ballabio, Andrea; Sacco, Francesca; Grumati, Paolo; Settembre, Carmine. - In: EMBO JOURNAL. - ISSN 0261-4189. - (2020), p. e105696. [10.15252/embj.2020105696]

MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B

Cinque, Laura;Iavazzo, Maria;Di Malta, Chiara;Cesana, Marcella;Conte, Ivan;Ballabio, Andrea;Grumati, Paolo;Settembre, Carmine
2020

Abstract

Lysosomal 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.
2020
MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B / Cinque, Laura; De Leonibus, Chiara; Iavazzo, Maria; Krahmer, Natalie; Intartaglia, Daniela; Salierno, Francesco Giuseppe; De Cegli, Rossella; Di Malta, Chiara; Svelto, Maria; Lanzara, Carmela; Maddaluno, Marianna; Wanderlingh, Luca Giorgio; Huebner, Antje K; Cesana, Marcella; Bonn, Florian; Polishchuk, Elena; Hübner, Christian A; Conte, Ivan; Dikic, Ivan; Mann, Matthias; Ballabio, Andrea; Sacco, Francesca; Grumati, Paolo; Settembre, Carmine. - In: EMBO JOURNAL. - ISSN 0261-4189. - (2020), p. e105696. [10.15252/embj.2020105696]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/814997
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 54
  • ???jsp.display-item.citation.isi??? 50
social impact