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The endoplasmic reticulum stress sensor IRE1 regulates collagen secretion through the enforcement of the proteostasis factor P4HB contributing to liver damage and fibrosis

ABSTRACT: Collagen is the most abundant protein in the cell and the main cargo of the secretory pathway, contributing to hepatic fibrogenesis due to extensive deposition of extracellular matrix (ECM). Here we investigated the possible contribution of the unfolded protein response (UPR), the main adaptive pathway that monitors and adjusts the protein production capacity at the endoplasmic reticulum (ER), to collagen biogenesis and liver disease. Genetic ablation of the ER stress sensor IRE1 reduced liver damage and diminished collagen deposition in models of liver fibrosis triggered by carbon tetrachloride (CCl4) administration or by high fat diet. Proteomic profiling identified the prolyl 4-hydroxylase (P4HB, also known as PDIA1), as a major IRE1-regulated gene, a critical factor involved in collagen maturation. Cell culture studies demonstrated that IRE1 deficiency results in collagen retention at the ER and altered secretion, a phenotype rescued by P4HB overexpression. Taken together, our results collectively establish a role of the IRE1/P4HB in the regulation of collagen production and its role in the pathogenesis of various disease states.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Valeria Garcia

LAB HEAD: Lars Plate

PROVIDER: PXD041444 | Pride | 2025-05-17

REPOSITORIES: Pride

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			Action	DRS
	02-001-VGL-20210630-Hetz-Red-TMT16.msf	Msf
	02-001-VGL-202120701-Hetz-Blue-TMT16.msf	Msf
	20210623-VGL-02-001_Hetz-Black_TMT16-.msf	Msf
	20210623-VGL-02-001_Hetz-Black_TMT16-0C_1.raw	Raw
	20210623-VGL-02-001_Hetz-Black_TMT16-100C_11.raw	Raw

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IRE1-dependent transcriptional change under a canonical endoplasmic-reticulum stressing stimulus and upon diauxic shift in Saccharomyces cerevisiae cells

Project description:Ire1 is an endoplasmic reticulum (ER)-located transmembrane protein that triggers the unfolded protein response. I recently noticed that Ire1 is activated not only in response to ER accumulation of unfolded proteins but also alongside diauxic shift in yeast Saccharomyces cerevisiae cells. I thus asked how different the Ire1-target genes upon two distinct scenes, a canonical ER -stressing stimuli and diauxic shift. Thus NGS transcriptome analysis was performed by using IRE1+ and ire1-delta mutant yeast cells under these conditions.

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Pharmacologic IRE1/XBP1s Activation Confers Targeted ER Proteostasis Reprogramming

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