Edem2, also known as endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2, is a key protein in the endoplasmic reticulum-associated degradation (ERAD) pathway. It is involved in the selection and degradation of misfolded proteins from the endoplasmic reticulum. Specifically, it plays a role in the mannose trimming of N-glycan in the ERAD of misfolded glycoproteins, which is crucial for maintaining endoplasmic reticulum homeostasis [2,4,5].

In a mouse model, Edem2 knockdown led to lipid droplet accumulation, higher levels of triglycerides and diglycerides in the myocardium, aggravating oxidative stress, hypertrophy, and the onset and progression of heart failure with preserved ejection fraction (HFpEF) under metabolic stress. This indicates that Edem2 is important in regulating cardiac lipid homeostasis [1]. In glioma cells, the knockdown of Edem2 decreased their invasive ability, suggesting its role in glioma cell invasion [3].

In conclusion, Edem2 is essential for ER-associated degradation processes, especially in mannose trimming of misfolded glycoproteins. The use of gene-knockout models, such as in mice and cell-based knockdown studies, has revealed its significant roles in diseases like HFpEF and glioma, highlighting its potential as a therapeutic target in these disease areas.

References:

1. Fonseka, Oveena, Raja, Rida, Ross, Claire, Müller, Oliver J, Liu, Wei. 2025. XBP1s-EDEM2 Prevents the Onset and Development of HFpEF by Ameliorating Cardiac Lipotoxicity. In Circulation, , . doi:10.1161/CIRCULATIONAHA.124.072194. https://pubmed.ncbi.nlm.nih.gov/40130322/

2. George, Ginto, Ninagawa, Satoshi, Yagi, Hirokazu, Okada, Tetsuya, Mori, Kazutoshi. 2020. EDEM2 stably disulfide-bonded to TXNDC11 catalyzes the first mannose trimming step in mammalian glycoprotein ERAD. In eLife, 9, . doi:10.7554/eLife.53455. https://pubmed.ncbi.nlm.nih.gov/32065582/

3. Wu, Yuxi, Wang, Haofei, Xiang, Wei, Yi, Dongye. 2023. EDEM2 is a diagnostic and prognostic biomarker and associated with immune infiltration in glioma: A comprehensive analysis. In Frontiers in oncology, 12, 1054012. doi:10.3389/fonc.2022.1054012. https://pubmed.ncbi.nlm.nih.gov/36727065/

4. Olivari, Silvia, Molinari, Maurizio. 2007. Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation of folding-defective glycoproteins. In FEBS letters, 581, 3658-64. doi:. https://pubmed.ncbi.nlm.nih.gov/17499246/

5. Ninagawa, Satoshi, Okada, Tetsuya, Sumitomo, Yoshiki, Yamamoto, Takashi, Mori, Kazutoshi. . EDEM2 initiates mammalian glycoprotein ERAD by catalyzing the first mannose trimming step. In The Journal of cell biology, 206, 347-56. doi:10.1083/jcb.201404075. https://pubmed.ncbi.nlm.nih.gov/25092655/