However, how SGIP1 plays in two seemingly unrelated cellular processes as regulators of energy balance as well as CME remains enigmatic. FCHo1/2 proteins are key endocytic initiators of clathrin-mediated endocytosis (CME) and contain a membrane-tubulating extended FCH/FCH and BAR domain (EFC/F-BAR) and a C-terminal μHD, which interacts with the endocytic adaptor/scaffold, Ede1/Eps15 ( Henne et al., 2010 Uezu et al., 2011). Previous studies identified SGIP1 as an ortholog of FCHo1/2 due to the similarity of its domain structure to that of FCHo proteins and its interaction with endocytic proteins Eps15 ( Fazioli et al., 1993), intersectin ( Dergai et al., 2010), and AP-2 ( Uezu et al., 2007 Hollopeter et al., 2014). SGIP1 consists of an N-terminal MP domain, followed by a proline-rich domain (PRD) and a C-terminal μ-homology domain (μHD) ( Figure 1A). Although it is not clear how SGIP1 acts as a regulator of energy balance, increased hypothalamic SGIP1 gene expression is known to be a common physiological feature of obesity and diabetes ( Trevaskis et al., 2005 Cummings et al., 2012). It was discovered in the hypothalamus of lean and obese Psammomys obesus (the Israel sand rat), and antisense against hypothalamic SGIP1 mRNA inhibited food intake and led to decreased bodyweight ( Trevaskis et al., 2005). SGIP1 is specifically expressed in the brain and is known to function in energy homeostasis ( Trevaskis et al., 2005). These findings suggest that caution should be taken in interpreting the role of SGIP1 in endocytosis. Thus, our results indicate that SGIP1α, but not SGIP1, is the functional ortholog of FCHos, and SGIP1 and SGIP1α are not functionally redundant. Moreover, only SGIP1α rescued endocytic defects caused by FCHo knock-down. Here, we report that the additional region in the MP is essential for SGIP1α to deform membrane into tubules and for homo-oligomerization, and SGIP1, which lacks this region, fails to perform these functions. Moreover, many previous studies have either inadvertently used SGIP1 instead of SGIP1α or used the different isoforms with or without additional regions indiscriminately, resulting in further confusion. SGIP1α is a longer splicing variant in mouse brains that contains additional regions in the membrane phospholipid-binding domain (MP) and C-terminal region, but functional consequences with or without additional regions between SGIP1 and SGIP1α remain elusive. Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1 (SGIP1), originally known as a regulator of energy homeostasis, was later found to be an ortholog of Fer/Cip4 homology domain-only (FCHo) proteins and to function during endocytosis. 3Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.2Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, South Korea.1Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.Sang-Eun Lee 1,2 ‡, Eunji Cho 1 ‡, Soomin Jeong 1 †, Yejij Song 1, Seokjo Kang 3 † and Sunghoe Chang 1,2*
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