Abstract

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. 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. 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. 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, only SGIP1α rescued endocytic defects caused by FCHo knock-down. Thus, our results indicate that SGIP1α, but not SGIP1, is the functional ortholog of FCHos, and SGIP1 and SGIP1α are not functionally redundant. These findings suggest that caution should be taken in interpreting the role of SGIP1 in endocytosis.

Highlights

  • AND RESULTSSGIP1 is expressed in the brain and is known to function in energy homeostasis (Trevaskis et al, 2005)

  • SGIP1 was identified as an ortholog of FCHo1/2, previous attempts to test whether SGIP1 can replace the function of Fer/ Cip4 homology domain-only (FCHo) proteins, resulted in conflicting findings (Henne et al, 2010; Hollopeter et al, 2014)

  • We have presented a series of experimental evidence that SGIP1 and its longer splicing variant, SGIP1α, are not functionally redundant, and that SGIP1α, not SGIP1, is a functional ortholog of FCHo proteins

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Summary

AND RESULTS

SGIP1 is expressed in the brain and is known to function in energy homeostasis (Trevaskis et al, 2005). EGFP-tagged SGIP1, SGIP1, which lacks additional regions, failed to do so, resulting in a diffuse cytoplasmic expression pattern (Figures 1B,C) These results suggest that the additional region in the MP domain is required for the membrane tubulating activity of SGIP1α. Since we found that the additional region in the MP domain is critical for the formation of homo-oligomers and membrane tubules (Figures 2B,C), we reasoned that the discrepancies may have arisen from the use of different splicing variants To test this idea, we knocked down FCHo2 in HeLa cells (Supplementary Figure S2A; Supplementary Table S2), in which FCHo2 is predominantly expressed and FCHo1 expression is virtually undetectable (Uezu et al, 2011; Umasankar et al, 2012; Umasankar et al, 2014). These results confirm that SGIP1α, not SGIP1, is a functional ortholog of FCHo1/2 and that SGIP1 and SGIP1α are not functionally redundant

DISCUSSION
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ETHICS STATEMENT
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