Tmem33, a transmembrane protein, has diverse essential functions. It is an endoplasmic reticulum (ER) transmembrane protein involved in multiple biological pathways such as lipid homeostasis, intracellular calcium homeostasis, and the unfolded protein response signaling. It also plays a role in angiogenesis, antiviral immunity, and is associated with various diseases including cancer and kidney-related disorders [1,2,4,6,7]. Genetic models like gene knockout (KO) mouse models can be valuable for studying Tmem33's functions.

In cancer cells, loss of PKM2 leads to up-regulation of Tmem33, which recruits RNF5 to promote SCAP degradation, regulating lipid homeostasis [1]. In renal tubular epithelial cells, Tmem33 interacts with polycystin-2, reducing intracellular calcium content and influencing autophagic flux and apoptosis [2]. In cervical cancer, high Tmem33 expression is associated with poor prognosis, and its knockdown suppresses cell proliferation and invasion [3,5]. In zebrafish, tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis [4]. In zebrafish liver cells, knockdown of Tmem33 increases host ifn transcription, as it negatively regulates virus-triggered interferon induction [6]. In the malaria parasite, targeted deletion of Tmem33 confirmed its importance for all life-cycle stages [8].

In conclusion, Tmem33 is crucial in various biological processes. Model-based research, especially KO studies, has revealed its roles in lipid metabolism, calcium homeostasis, cancer development, angiogenesis, antiviral immunity, and malaria parasite development. Understanding Tmem33 provides insights into disease mechanisms and potential therapeutic targets in these areas.

References:

1. Liu, Fabao, Ma, Min, Gao, Ang, Li, Lingjun, Xu, Wei. 2021. PKM2-TMEM33 axis regulates lipid homeostasis in cancer cells by controlling SCAP stability. In The EMBO journal, 40, e108065. doi:10.15252/embj.2021108065. https://pubmed.ncbi.nlm.nih.gov/34487377/

2. Arhatte, Malika, Gunaratne, Gihan S, El Boustany, Charbel, Honoré, Eric, Patel, Amanda. 2019. TMEM33 regulates intracellular calcium homeostasis in renal tubular epithelial cells. In Nature communications, 10, 2024. doi:10.1038/s41467-019-10045-y. https://pubmed.ncbi.nlm.nih.gov/31048699/

3. Zhang, Hui, Wang, Jun, Yang, Ji, Zhao, Jian, Wang, Xiu. 2023. TMEM33 as a Prognostic Biomarker of Cervical Cancer and Its Correlation with Immune Infiltration. In Mediators of inflammation, 2023, 5542181. doi:10.1155/2023/5542181. https://pubmed.ncbi.nlm.nih.gov/37273452/

4. Savage, Aaron M, Kurusamy, Sathishkumar, Chen, Yan, Chico, Timothy J A, Wilkinson, Robert N. 2019. tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis. In Nature communications, 10, 732. doi:10.1038/s41467-019-08590-7. https://pubmed.ncbi.nlm.nih.gov/30760708/

5. Chen, Hanxiang, Zhao, Xia, Li, Yongqing, Wang, Lili, Ma, Wanshan. 2022. High Expression of TMEM33 Predicts Poor Prognosis and Promotes Cell Proliferation in Cervical Cancer. In Frontiers in genetics, 13, 908807. doi:10.3389/fgene.2022.908807. https://pubmed.ncbi.nlm.nih.gov/35832191/

6. Lu, Long-Feng, Zhang, Can, Li, Zhuo-Cong, Zhou, Fang, Li, Shun. 2021. A novel role of Zebrafish TMEM33 in negative regulation of interferon production by two distinct mechanisms. In PLoS pathogens, 17, e1009317. doi:10.1371/journal.ppat.1009317. https://pubmed.ncbi.nlm.nih.gov/33600488/

7. Sakabe, Isamu, Hu, Rong, Jin, Lu, Clarke, Robert, Kasid, Usha N. 2015. TMEM33: a new stress-inducible endoplasmic reticulum transmembrane protein and modulator of the unfolded protein response signaling. In Breast cancer research and treatment, 153, 285-97. doi:10.1007/s10549-015-3536-7. https://pubmed.ncbi.nlm.nih.gov/26268696/

8. Kamil, Mohd, Kina, Umit Yasar, Atmaca, Habibe Nur, Burak, Pinar, Aly, Ahmed S I. 2024. Endoplasmic reticulum localized TMEM33 domain-containing protein is crucial for all life cycle stages of the malaria parasite. In Molecular microbiology, 121, 767-780. doi:10.1111/mmi.15228. https://pubmed.ncbi.nlm.nih.gov/38238886/