Dataset Information

The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPRER.

ABSTRACT: Cells have evolved complex mechanisms to maintain protein homeostasis, such as the UPRER, which are strongly associated with several diseases and the aging process. We performed a whole-genome CRISPR-based knockout (KO) screen to identify genes important for cells to survive ER-based protein misfolding stress. We identified the cell-surface hyaluronidase (HAase), Transmembrane Protein 2 (TMEM2), as a potent modulator of ER stress resistance. The breakdown of the glycosaminoglycan, hyaluronan (HA), by TMEM2 within the extracellular matrix (ECM) altered ER stress resistance independent of canonical UPRER pathways but dependent upon the cell-surface receptor, CD44, a putative HA receptor, and the MAPK cell-signaling components, ERK and p38. Last, and most surprisingly, ectopic expression of human TMEM2 in C. elegans protected animals from ER stress and increased both longevity and pathogen resistance independent of canonical UPRER activation but dependent on the ERK ortholog mpk-1 and the p38 ortholog pmk-1.

SUBMITTER: Schinzel RT

PROVIDER: S-EPMC6913896 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPR<sup>ER</sup>.

Schinzel Robert Thomas RT Higuchi-Sanabria Ryo R Shalem Ophir O Moehle Erica Ann EA Webster Brant Michael BM Joe Larry L Bar-Ziv Raz R Frankino Phillip Andrew PA Durieux Jenni J Pender Corinne C Kelet Naame N Kumar Saranya Santhosh SS Savalia Nupur N Chi Hannah H Simic Milos M Nguyen Ngoc-Tram NT Dillin Andrew A

Cell 20191121 6

Cells have evolved complex mechanisms to maintain protein homeostasis, such as the UPR<sup>ER</sup>, which are strongly associated with several diseases and the aging process. We performed a whole-genome CRISPR-based knockout (KO) screen to identify genes important for cells to survive ER-based protein misfolding stress. We identified the cell-surface hyaluronidase (HAase), Transmembrane Protein 2 (TMEM2), as a potent modulator of ER stress resistance. The breakdown of the glycosaminoglycan, hya ...[more]

PMID: 31761535

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Project description:Schmid metaphyseal chondrodysplasia (MCDS) involves dwarfism and growth plate cartilage hypertrophic zone expansion resulting from dominant mutations in the hypertrophic zone collagen, Col10a1. Mouse models phenocopying MCDS through the expression of an exogenous misfolding protein in the endoplasmic reticulum (ER) in hypertrophic chondrocytes have demonstrated the central importance of ER stress in the pathology of MCDS. The resultant unfolded protein response (UPR) in affected chondrocytes involved activation of canonical ER stress sensors, IRE1, ATF6, and PERK with the downstream effect of disrupted chondrocyte differentiation. Here, we investigated the role of the highly conserved IRE1/XBP1 pathway in the pathology of MCDS. Mice with a MCDS collagen X p.N617K knock-in mutation (ColXN617K) were crossed with mice in which Xbp1 was inactivated specifically in cartilage (Xbp1Cart?Ex2), generating the compound mutant, C/X. The severity of dwarfism and hypertrophic zone expansion in C/X did not differ significantly from ColXN617K, revealing surprising redundancy for the IRE1/XBP1 UPR pathway in the pathology of MCDS. Transcriptomic analyses of hypertrophic zone cartilage identified differentially expressed gene cohorts in MCDS that are pathologically relevant (XBP1-independent) or pathologically redundant (XBP1-dependent). XBP1-independent gene expression changes included large-scale transcriptional attenuation of genes encoding secreted proteins and disrupted differentiation from proliferative to hypertrophic chondrocytes. Moreover, these changes were consistent with disruption of C/EBP-?, a master regulator of chondrocyte differentiation, by CHOP, a transcription factor downstream of PERK that inhibits C/EBP proteins, and down-regulation of C/EBP-? transcriptional co-factors, GADD45-? and RUNX2. Thus we propose that the pathology of MCDS is underpinned by XBP1 independent UPR-induced dysregulation of C/EBP-?-mediated chondrocyte differentiation. Our data suggest that modulation of C/EBP-? activity in MCDS chondrocytes may offer therapeutic opportunities.

Dataset Information

The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPRER.

Publications

The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPR<sup>ER</sup>.

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Dataset Information

The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPRER.

Publications

The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPR&lt;sup&gt;ER&lt;/sup&gt;.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

The Hyaluronidase, TMEM2, Promotes ER Homeostasis and Longevity Independent of the UPR<sup>ER</sup>.