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

stress response endoplasmic reticulum aging crispr-cas9 mapk signaling immune response extracellular matrix glucosaminoglycan

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#1 Engadin

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Posted 22 November 2019 - 07:33 PM


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B E H I N D   P A Y W A L L   S O U R C E :   Cell

 

 

 

 

 

 

Highlights
 
• CRISPR-Cas9 screening in human fibroblasts reveals TMEM2 as a regulator of ER stress
 
• TMEM2 alters intracellular ER stress resistance through changes in ECM metabolism
 
• TMEM2 promotes ER stress resistance independent of UPR ER through MAPK signaling
 
• Ectopic expression of human TMEM2 promotes lifespan and immunity in C. elegans
 
 
Summary
 
Cells have evolved complex mechanisms to maintain protein homeostasis, such as the UPR ER, 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 UPR ER 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 UPR ER activation but dependent on the ERK ortholog mpk-1 and the p38 ortholog pmk-1.

 

 

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Also tagged with one or more of these keywords: stress response, endoplasmic reticulum, aging, crispr-cas9, mapk signaling, immune response, extracellular matrix, glucosaminoglycan

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