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.

中文翻译：

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透明质酸酶 TMEM2 促进 ER 稳态和独立于 UPRER 的长寿。

细胞已经进化出复杂的机制来维持蛋白质稳态，例如与多种疾病和衰老过程密切相关的 UPRER。我们进行了基于 CRISPR 的全基因组敲除 (KO) 筛选，以鉴定对细胞在基于 ER 的蛋白质错误折叠压力下存活很重要的基因。我们将细胞表面透明质酸酶 (HAase)、跨膜蛋白 2 (TMEM2) 鉴定为内质网应激抗性的有效调节剂。细胞外基质 (ECM) 内的 TMEM2 对糖胺聚糖、透明质酸 (HA) 的分解改变了 ER 应激抗性，这与经典的 UPRER 途径无关，但依赖于细胞表面受体 CD44、推定的 HA 受体和 MAPK 细胞-信号成分，ERK 和 p38。最后，也是最令人惊讶的是，人类 TMEM2 在 C 中的异位表达。