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

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.

A Futile Battle? Protein Quality Control and the Stress of Aging.

There exists a phenomenon in aging research whereby early life stress can have positive impacts on longevity. The mechanisms underlying these observations suggest a robust, long-lasting induction of cellular defense mechanisms. These include the various unfolded protein responses of the endoplasmic reticulum (ER), cytosol, and mitochondria. Indeed, ectopic induction of these pathways, in the absence of stress, is sufficient to increase lifespan in organisms as diverse as yeast, worms, and flies. Here, we provide an overview of the protein quality control mechanisms that operate in the cytosol, mitochondria, and ER and discuss how they affect cellular health and viability during stress and aging.