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, that are strongly associated with several diseases and the aging process. We performed a whole genome CRISPR-based knockout screen to identify genes important for cells to survive ER-based protein misfolding stress. We identified the cell-surface hyaluronidase, 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. Lastly, 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.

细胞已演化出维持蛋白质稳态（protein homeostasis）的复杂调控机制，例如内质网未折叠蛋白反应（UPRER），此类机制与多种疾病及衰老进程紧密相关。我们实施了基于CRISPR的全基因组敲除筛选，以鉴定出对细胞抵御内质网（ER）源性蛋白质错误折叠应激至关重要的基因。我们鉴定出细胞表面透明质酸酶——跨膜蛋白2（TMEM2），其为内质网应激抗性的强效调控因子。TMEM2在细胞外基质（ECM）中降解糖胺聚糖透明质酸（HA），其所介导的内质网应激抗性变化不依赖于经典UPRER通路，但依赖于细胞表面受体CD44（一种推定的透明质酸受体）以及丝裂原活化蛋白激酶（MAPK）细胞信号通路组分ERK与p38。最后，也是最令人意外的是，在秀丽隐杆线虫（C. elegans）中异位表达人类TMEM2，可保护线虫抵御内质网应激，并延长其寿命、增强病原体抗性；该效应不依赖于经典UPRER的激活，但依赖于ERK同源基因mpk-1与p38同源基因pmk-1。