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Inner nuclear membrane protein TMEM201 maintains endothelial cell migration and angiogenesis by interacting with the LINC complex
Yutian Zhang1,2,† , Ya Kong1,2,† , Haoran Guo1,2 , Yun Liu3 , Yi Zang1,2,4,* , Jia Li1,2,3,4,5,*
1University of Chinese Academy of Sciences, Beijing 100049, China
2State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China
4School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
5Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China
These authors contributed equally to this work
*Correspondence to:Yi Zang ,; Jia Li ,
J Mol Cell Biol, Volume 14, Issue 3, March 2022, mjac017,
Keyword: transmembrane protein 201, inner nuclear membrane, LINC complex, endothelial cell, migration, angiogenesis

The nuclear envelope comprises the outer nuclear membrane, inner nuclear membrane (INM), and nucleopore. Although ∼60 INM proteins have been identified, only a few of them have been well characterized, revealing their crucial roles. Our group focused on the INM protein transmembrane protein 201 (TMEM201), whose role in cellular function remains to be defined. In this study, we investigated the role of TMEM201 in endothelial cell migration and angiogenesis. Depletion of TMEM201 expression by short hairpin RNA-mediated interference impeded human umbilical vein endothelial cell (HUVEC) angiogenic behavior in tube formation and fibrin gel bead sprouting assays. Meanwhile, TMEM201-deficient HUVECs exhibited impaired migration ability. We next explored the underlying mechanism and found that the N-terminal of TMEM201 interacted with the linker of nucleoskeleton and cytoskeleton complex and was required for regulating endothelial cell migration and angiogenesis. These in vitro findings were further confirmed by using in vivo models. In Tmem201-knockout mice, retinal vessel development was arrested and aortic ring sprouting was defective. In addition, loss of tmem201 impaired zebrafish intersegmental vessel development. In summary, TMEM201 was shown to regulate endothelial cell migration and control the process of angiogenesis. This study is the first to reveal the role of INM proteins in the vascular system and angiogenesis.