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:Hyaluronan (HA) is a major extracellular matrix component whose tissue levels are dynamically regulated during embryonic development. Although the synthesis of HA has been shown to exert a substantial influence on embryonic morphogenesis, the functional importance of the catabolic aspect of HA turnover is poorly understood. Here, we demonstrate that the transmembrane hyaluronidase TMEM2 plays an essential role in neural crest development and the morphogenesis of neural crest derivatives, as evidenced by the presence of severe craniofacial abnormalities in Wnt1-Cre-mediated Tmem2 knockout (Tmem2CKO) mice. Neural crest cells (NCCs) are a migratory population of cells that gives rise to diverse cell lineages, including the craniofacial complex, the peripheral nervous system, and part of the heart. Analysis of Tmem2 expression during NCC formation and migration reveals that Tmem2 is expressed at the site of NCC delamination and in emigrating Sox9-positive NCCs. In Tmem2CKO embryos, the number of NCCs emigrating from the neural tube is greatly reduced. Furthermore, linage tracing reveals that the number of NCCs traversing the ventral migration pathway and the number of post-migratory neural crest derivatives are both significantly reduced in a Tmem2CKO background. In vitro studies using Tmem2-depleted mouse O9-1 neural crest cells demonstrate that Tmem2 expression is essential for the ability of these cells to form focal adhesions on and to migrate into HA-containing substrates. Additionally, we show that Tmem2-deficient NCCs exhibit increased apoptotic cell death in NCC-derived tissues, an observation that is corroborated by in vitro experiments using O9-1 cells. Collectively, our data demonstrate that TMEM2-mediated HA degradation plays an essential role in normal neural crest development. This study reveals the hitherto unrecognized functional importance of HA degradation in embryonic development and highlights the pivotal role of Tmem2 in the developmental process.

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>.