| Literature DB >> 31761535 |
Robert Thomas Schinzel1, Ryo Higuchi-Sanabria1, Ophir Shalem1, Erica Ann Moehle1, Brant Michael Webster1, Larry Joe1, Raz Bar-Ziv1, Phillip Andrew Frankino1, Jenni Durieux1, Corinne Pender1, Naame Kelet1, Saranya Santhosh Kumar2, Nupur Savalia1, Hannah Chi1, Milos Simic1, Ngoc-Tram Nguyen1, Andrew Dillin3.
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.Entities:
Keywords: CRISPR-Cas9; MAPK signaling; aging; endoplasmic reticulum; extracellular matrix; glucosaminoglycan; immune response; stress response
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Year: 2019 PMID： 31761535 PMCID： PMC6913896 DOI： 10.1016/j.cell.2019.10.018
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582