BioE COLLOQUIA SERIES: "Transcriptional Regulation of Selective Autophagy Controls Vertebrate Development and Growth"


Event details

Date and time 17.02.2020 12:15  
Place and room
Speaker Prof. Carmine Settembre, Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli/Naples (I)
Category Conferences - Seminars
(sandwiches served)

Organismal development and growth rely on biosynthetic, anabolic, processes. Whether also degradative, catabolic, pathways contribute to growth is still largely unknown. My laboratory has recently demonstrated that (macro)autophagy, a catabolic process that delivers cytosolic materials to lysosome for their degradation, plays a fundamental role in chondrocytes during bone growth (Cinque et al. Nature 2015). We found that chondrocytes sustain endoplasmic reticulum (ER) functions and pro-collagen secretion through the selective degradation of ER fragments via autophagy (ER-phagy). In particular, ER-phagy delivers non-native, ER-resident, pro-collagen molecules to lysosomes through the synergistic activity of the ER chaperone Calnexin (CNX) and the ER membrane protein FAM134B (Forrester et al. EMBO 2019).
Currently, we are investigating how ER-phagy is regulated in response to both metabolic and developmental cues. By combining Crispr/Cas9 technology to -omics approaches we found that ER-phagy is a transcriptional-regulated process, largely controlled by TFEB and TFE3 transcription factors.  TFEB/3 induce the expression of FAM134B and promote ER-phagy activation upon prolonged nutrient starvation. In addition, we discovered that this pathway is activated in chondrocytes by FGF signaling, a critical regulator of bone development. FGF signaling induces JNK-dependent proteasomal degradation of the insulin receptor substrate 1, which inhibits the insulin-PI3K-PKB/Akt-mTORC1 pathway and promotes TFEB/TFE3 nuclear translocation and FAM134B induction. FGF signaling controls ER-phagy both in medaka fish and mouse cartilage, hence suggesting that this pathway is physiologically relevant and evolutionarily conserved. Thus, our studies identify ER-phagy as new biological process required for organismal development and growth.

De Leonibus C, Cinque L, Settembre C. Emerging lysosomal pathways for quality control at the endoplasmic reticulum. FEBS letters 593: 2319-2329 (2019).
Cinque L, Forrester A et al. FGF signalling regulates bone growth through autophagy. Nature 528, 272–275 (2015).
Forrester A, De Leonibus C et al. A selective ER-phagy exerts procollagen quality control via a Calnexin-FAM134B complex. EMBO J. 38, (2019)

The main research interest of the Settembre laboratory is to understand the regulation and the role of the lysosomal-autophagy pathway in both physiological and disease processes. In particular, keeping in mind that the lysosomal-autophagy pathway is dynamically regulated in response to changes in the extracellular environment, the lab is exploring the hypothesis that the developmental regulation of this pathway is an important contributor to organismal development and growth. Using a combination of mouse genetics, cell biology and pharmacological approaches, the Settembre lab has recently demonstrated that autophagy is induced in growing bones during post-natal development and regulates the secretion of collagens, the major components of cartilage ECM. The post-natal induction of autophagy is mediated by the FGF signaling, demonstrating that growth factor signalling can promote organismal growth through the activation of autophagy. The lab's studies will have the potential to identify new pathways through which growth factors regulate cellular catabolism, to explain how catabolic processes support anabolic pathways in vivo, and to provide proof of principle that developmental disorders may be treated by modulation of cellular metabolism.

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