Sestrin2 Drives ER-phagy in Response to Protein Misfolding

Overview

Journal Dev Cell

Publisher Cell Press

Specialties Cell Biology
Reproductive Medicine

Date 2024 Aug 2

PMID 39094564

Authors

Chiara De Leonibus

Marianna Maddaluno

Rosa Ferriero

Roberta Besio

Laura Cinque

Pei Jin Lim

Alessandro Palma

Rossella De Cegli

Salvatore Gagliotta

Sandro Montefusco

Maria Iavazzo

Marianne Rohrbach

Cecilia Giunta

Elena Polishchuk

Diego Louis Medina

Diego di Bernardo

Antonella Forlino

Pasquale Piccolo

Carmine Settembre

Affiliations

Soon will be listed here.

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.

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