Tmem41b-KO Mouse

TMEM41B, also known as Stasimon, is an endoplasmic reticulum (ER)-localized transmembrane protein with phospholipid scramblase activity. It plays crucial roles in multiple biological processes, including lipoprotein biogenesis, lipid homeostasis, autophagosome formation, and is involved in various viral infection pathways [2,4,5,9].

Genetic studies, especially knockout (KO) models, have been instrumental in revealing its functions. Hepatic TMEM41B KO eliminates plasma lipids due to absent mature lipoproteins in the ER, yet paradoxically activates lipid production, leading to non-alcoholic hepatosteatosis in mice [2]. In the context of viral infections, TMEM41B KO cells show impaired double-membrane vesicle (DMV) formation during β-coronavirus infection, and reduced flavivirus and SARS-CoV-2 infection [1,3]. In dengue virus and human coronavirus OC43 infections, TMEM41B-deficient cells have diminished viral replication, accompanied by upregulation of innate immune dsRNA sensors [6]. Knockdown of TMEM41B also suppresses Pseudorabies virus proliferation by affecting viral entry and lipid-regulated processes [7]. Postnatal depletion of TMEM41B in a conditional knockout (CKO) mouse model arrests weight gain, causes motor dysfunction, and leads to death, while also severely affecting cell proliferation in mouse embryonic fibroblasts [8].

In summary, TMEM41B is essential for maintaining lipid homeostasis, normal cell proliferation, and survival, and plays a significant role in facilitating viral infections. The KO and CKO mouse models have provided valuable insights into its functions in these processes, which could potentially contribute to the development of strategies for treating diseases related to lipid metabolism disorders and viral infections.

References:

1. Hoffmann, H-Heinrich, Schneider, William M, Rozen-Gagnon, Kathryn, Poirier, John T, Rice, Charles M. 2020. TMEM41B Is a Pan-flavivirus Host Factor. In Cell, 184, 133-148.e20. doi:10.1016/j.cell.2020.12.005. https://pubmed.ncbi.nlm.nih.gov/33338421/

2. Huang, Dong, Xu, Bolin, Liu, Lu, Reinisch, Karin, Chen, Xiao-Wei. 2021. TMEM41B acts as an ER scramblase required for lipoprotein biogenesis and lipid homeostasis. In Cell metabolism, 33, 1655-1670.e8. doi:10.1016/j.cmet.2021.05.006. https://pubmed.ncbi.nlm.nih.gov/34015269/

3. Ji, Mingming, Li, Meng, Sun, Long, Deng, Hongyu, Zhao, Yan G. 2022. VMP1 and TMEM41B are essential for DMV formation during β-coronavirus infection. In The Journal of cell biology, 221, . doi:10.1083/jcb.202112081. https://pubmed.ncbi.nlm.nih.gov/35536318/

4. Zhang, Tizhong, Li, Yang E, Yuan, Yiqiong, Yang, Hongyuan, Qi, Shiqian. 2021. TMEM41B and VMP1 are phospholipid scramblases. In Autophagy, 17, 2048-2050. doi:10.1080/15548627.2021.1937898. https://pubmed.ncbi.nlm.nih.gov/34074213/

5. Li, Yang Emma, Wang, Yichang, Du, Ximing, Qi, Shiqian, Yang, Hongyuan. . TMEM41B and VMP1 are scramblases and regulate the distribution of cholesterol and phosphatidylserine. In The Journal of cell biology, 220, . doi:10.1083/jcb.202103105. https://pubmed.ncbi.nlm.nih.gov/33929485/

6. Yousefi, Meisam, Lee, Wai Suet, Yan, Biaoguo, Chan, Kuan Rong, Ooi, Yaw Shin. 2022. TMEM41B and VMP1 modulate cellular lipid and energy metabolism for facilitating dengue virus infection. In PLoS pathogens, 18, e1010763. doi:10.1371/journal.ppat.1010763. https://pubmed.ncbi.nlm.nih.gov/35939522/

7. Li, Xiu-Qing, Zeng, Lei, Liang, Dong-Ge, Chu, Bei-Bei, Wang, Jiang. 2023. TMEM41B Is an Interferon-Stimulated Gene That Promotes Pseudorabies Virus Replication. In Journal of virology, 97, e0041223. doi:10.1128/jvi.00412-23. https://pubmed.ncbi.nlm.nih.gov/37255475/

8. Carlini, Maria J, Van Alstyne, Meaghan, Yang, Hua, Shneider, Neil A, Pellizzoni, Livio. 2024. Stasimon/Tmem41b is required for cell proliferation and adult mouse survival. In Biochemical and biophysical research communications, 712-713, 149923. doi:10.1016/j.bbrc.2024.149923. https://pubmed.ncbi.nlm.nih.gov/38640735/

9. Morita, Keigo, Hama, Yutaro, Mizushima, Noboru. 2019. TMEM41B functions with VMP1 in autophagosome formation. In Autophagy, 15, 922-923. doi:10.1080/15548627.2019.1582952. https://pubmed.ncbi.nlm.nih.gov/30773971/