Hou Wenyang, Gupta Swati, Beauchamp Marie-Claude, Yuan Libin, Jerome-Majewska Loydie A
Department of Human Genetics, McGill University, Montreal, Québec, Canada.
Department of Pediatrics, McGill University Health Centre Glen Site, Montreal, Québec, Canada.
PLoS One. 2017 Aug 10;12(8):e0182995. doi: 10.1371/journal.pone.0182995. eCollection 2017.
The transmembrane emp24 domain/p24 (TMED) family are essential components of the vesicular transport machinery. Members of the TMED family serve as cargo receptors implicated in selection and packaging of endoplasmic reticulum (ER) luminal proteins into coatomer (COP) II coated vesicles for anterograde transport to the Golgi. Deletion or mutations of Tmed genes in yeast and Drosophila results in ER-stress and activation of the unfolded protein response (UPR). The UPR leads to expression of genes and proteins important for expanding the folding capacity of the ER, degrading misfolded proteins, and reducing the load of new proteins entering the ER. The UPR is activated in non-alcoholic fatty liver disease (NAFLD) in human and mouse and may contribute to the development and the progression of NAFLD. Tmed2, the sole member of the vertebrate Tmed β subfamily, exhibits tissue and temporal specific patterns of expression in embryos and developing placenta but is ubiquitously expressed in all adult organs. We previously identified a single point mutation, the 99J mutation, in the signal sequence of Tmed2 in an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Histological and molecular analysis of livers from heterozygous mice carrying the 99J mutation, Tmed299J/+, revealed a requirement for TMED2 in liver health. We show that Tmed299J/+ mice had decreased levels of TMED2 and TMED10, dilated endoplasmic reticulum membrane, and increased phosphorylation of eIF2α, indicating ER-stress and activation of the UPR. Increased expression of Srebp1a and 2 at the newborn stage and increased incidence of NAFLD were also found in Tmed299J/+ mice. Our data establishes Tmed299J/+ mice as a novel mouse model for NAFLD and supports a role for TMED2 in liver health.
跨膜emp24结构域/p24（TMED）家族是囊泡运输机制的重要组成部分。TMED家族成员作为货物受体，参与将内质网（ER）腔蛋白分选和包装到II型被膜小泡（COP II）中，以便顺向运输至高尔基体。酵母和果蝇中Tmed基因的缺失或突变会导致内质网应激和未折叠蛋白反应（UPR）的激活。UPR会导致一些基因和蛋白质的表达，这些基因和蛋白质对于扩大内质网的折叠能力、降解错误折叠的蛋白质以及减少进入内质网的新蛋白质负载至关重要。UPR在人类和小鼠的非酒精性脂肪性肝病（NAFLD）中被激活，可能在NAFLD的发生和发展中起作用。Tmed2是脊椎动物Tmed β亚家族的唯一成员，在胚胎和发育中的胎盘中呈现出组织和时间特异性的表达模式，但在所有成年器官中均普遍表达。我们之前在N-乙基-N-亚硝基脲（ENU）诱变筛选中，在Tmed2的信号序列中鉴定出一个单点突变，即99J突变。对携带99J突变的杂合小鼠（Tmed299J/+）肝脏进行的组织学和分子分析表明，TMED2对肝脏健康至关重要。我们发现Tmed299J/+小鼠的TMED2和TMED10水平降低，内质网膜扩张，eIF2α磷酸化增加，表明存在内质网应激和UPR的激活。在Tmed299J/+小鼠的新生阶段还发现Srebp1a和2的表达增加以及NAFLD的发病率增加。我们的数据将Tmed299J/+小鼠确立为一种新的NAFLD小鼠模型，并支持TMED2在肝脏健康中的作用。
