小柯机器人

美国加州大学伯克利分校Andrew Dillin课题组最新研究显示，透明质酸酶(HAase)-TMEM2(跨膜蛋白2)不依赖内质网未折叠蛋白应答（UPR^ER）促进内质网稳态和长寿。11月21日，国际学术期刊《细胞》在线发表了这一成果。

研究人员进行了基于全基因组CRISPR的敲除（KO）筛选，以鉴定对细胞生存的重要基因，这些基因能够抵抗来自内质网（ER）的蛋白质错误折叠压力。研究人员发现细胞表面透明质酸酶TMEM2是作为内质网应激抗性的有效调节剂。TMEM2在细胞外基质（ECM）中对糖胺聚糖透明质酸（HA）的破坏改变了ER的抗逆性，这与经典的UPR^ER途径无关，而是取决于细胞表面受体-CD44（可能是HA的受体）和MAPK信号通路的组分ERK和p38。

最后，也是最令人意外的是，秀丽隐杆线虫中人TMEM2的异位表达使动物免受内质网应激并增加了寿命和病原体抗性，这种作用不受经典UPRER激活的调控，而是依赖于ERK直系同源蛋白mpk-1和p38直系同源蛋白pmk-1。

据介绍，细胞已经进化出维持蛋白质稳态的复杂机制，例如UPR^ER，该途径与多种疾病和衰老过程密切相关。

附：英文原文

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

Author: Robert Thomas Schinzel, Ryo Higuchi-Sanabria, Ophir Shalem, Erica Ann Moehle, Brant Michael Webster, Larry Joe, Raz Bar-Ziv, Phillip Andrew Frankino, Jenni Durieux, Corinne Pender, Naame Kelet, Saranya Santhosh Kumar, Nupur Savalia, Hannah Chi, Milos Simic, Ngoc-Tram Nguyen, Andrew Dillin

Issue&Volume: November 21, 2019

Abstract: Cells have evolved complex mechanisms to maintain protein homeostasis, such as theUPRER, which are strongly associated with several diseases and the aging process. We performeda whole-genome CRISPR-based knockout (KO) screen to identify genes important for cellsto 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 extracellularmatrix (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 resistanceindependent of canonical UPRER activation but dependent on the ERK ortholog mpk-1 and the p38 ortholog pmk-1.

DOI: 10.1016/j.cell.2019.10.018

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)31168-7