Sestrin2 drives ER-phagy in response to protein misfolding

  • Dev Cell. 2024 Aug 19;59(16):2035-2052.e10. doi: 10.1016/j.devcel.2024.07.004.
Chiara De Leonibus  1 ,  Marianna Maddaluno  2 ,  Rosa Ferriero  3 ,  Roberta Besio  4 ,  Laura Cinque  2 ,  Pei Jin Lim  5 ,  Alessandro Palma  3 ,  Rossella De Cegli  3 ,  Salvatore Gagliotta  3 ,  Sandro Montefusco  3 ,  Maria Iavazzo  2 ,  Marianne Rohrbach  5 ,  Cecilia Giunta  5 ,  Elena Polishchuk  3 ,  Diego Louis Medina  6 ,  Diego Di Bernardo  7 ,  Antonella Forlino  4 ,  Pasquale Piccolo  3 ,  Carmine Settembre  8
Affiliations
  • 1. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Department of Health Sciences, University of Basilicata, Potenza, Italy.
  • 2. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
  • 3. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
  • 4. Department of Molecular Medicine, University of Pavia, Pavia, Italy.
  • 5. Division of Metabolism and Children's Research Center, University Hospital of Zurich, Zurich, Switzerland.
  • 6. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Department of Translational Medical Sciences, Federico II University, Naples, Italy.
  • 7. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Department of Chemical, Materials and Industrial Production Engineering, University of Naples "Federico II", Naples, Italy.
  • 8. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy; Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy. Electronic address: [email protected].
PMID: 39094564 DOI: 10.1016/j.devcel.2024.07.004
Abstract

Protein biogenesis within the endoplasmic reticulum (ER) is crucial for organismal function. Errors during protein folding necessitate the removal of faulty products. ER-associated protein degradation and ER-phagy target misfolded proteins for proteasomal and lysosomal degradation. The mechanisms initiating ER-phagy in response to ER proteostasis defects are not well understood. By studying mouse primary cells and patient samples as a model of ER storage disorders (ERSDs), we show that accumulation of faulty products within the ER triggers a response involving SESTRIN2, a nutrient sensor controlling mTORC1 signaling. SESTRIN2 induction by XBP1 inhibits mTORC1's phosphorylation of TFEB/TFE3, allowing these transcription factors to enter the nucleus and upregulate the ER-phagy receptor FAM134B along with lysosomal genes. This response promotes ER-phagy of misfolded proteins via FAM134B-Calnexin complex. Pharmacological induction of FAM134B improves clearance of misfolded proteins in ERSDs. Our study identifies the interplay between nutrient signaling and ER quality control, suggesting therapeutic strategies for ERSDs.

Keywords
ER storage disorders; ER-phagy; FAM134B; TFEB; alpha(1)-antitrypsin Z (alpha(1)-ATZ); autophagy; collagen; endoplasmic reticulum; mTORC1; quality control.
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