Regulation of the actin cytoskeleton by the Ndel1-Tara complex is critical for cell migration.

Ji-Ho Hong,Seol-Ae Lee,Yeongjun Suh,Dong Jin Mun,Yongdo Kwak,Bo Kyoung Suh,Minh Dang Nguyen,Haeryun Lee,Bon Seong Goo,Cana Park,Youngsik Woo,Kamon Sanada,Sang Ki Park,Sung Jin Park

doi:10.1038/srep31827

Abstract

Nuclear distribution element-like 1 (Ndel1) plays pivotal roles in diverse biological processes and is implicated in the pathogenesis of multiple neurodevelopmental disorders. Ndel1 function by regulating microtubules and intermediate filaments; however, its functional link with the actin cytoskeleton is largely unknown. Here, we show that Ndel1 interacts with TRIO-associated repeat on actin (Tara), an actin-bundling protein, to regulate cell movement. In vitro wound healing and Boyden chamber assays revealed that Ndel1- or Tara-deficient cells were defective in cell migration. Moreover, Tara overexpression induced the accumulation of Ndel1 at the cell periphery and resulted in prominent co-localization with F-actin. This redistribution of Ndel1 was abolished by deletion of the Ndel1-interacting domain of Tara, suggesting that the altered peripheral localization of Ndel1 requires a physical interaction with Tara. Furthermore, co-expression of Ndel1 and Tara in SH-SY5Y cells caused a synergistic increase in F-actin levels and filopodia formation, suggesting that Tara facilitates cell movement by sequestering Ndel1 at peripheral structures to regulate actin remodeling. Thus, we demonstrated that Ndel1 interacts with Tara to regulate cell movement. These findings reveal a novel role of the Ndel1-Tara complex in actin reorganization during cell movement.

Highlights

Understanding of Ndel[1] function is mostly associated with microtubule dynamics, whereas knowledge of its link to actin filaments is limited[19,32,33,34]
In a yeast two-hybrid screen using human Ndel[1] as bait, TRIO-associated repeat on actin (Tara) was identified as a positive clone (Fig. 1A); we obtained a full-length cDNA clone of Tara by RT-PCR using total RNA isolated from HEK293 cells as a template
When Tara was co-expressed, there were no significant changes in the interactions between Ndel[1] and Disc[1] (Fig. S1I) or Ndel[1] and Lis[1] (Fig. S1J), which was the case for Ndel[1] in the interaction between Tara and Trio1118–1919, which is known as the binding region of Trio for Tara[35] (Fig. S1K)

Summary

Introduction

Understanding of Ndel[1] function is mostly associated with microtubule dynamics, whereas knowledge of its link to actin filaments is limited[19,32,33,34]. TRIO binding protein-1 (TRIOBP-1), known as TRIO-associated repeat on actin (Tara), is a filamentous actin (F-actin)-binding protein that was originally identified as a TRIO-associated factor. As an interacting partner of TRIO, TRIOBP-1 is linked to actin cytoskeleton organization, and a deficiency of this protein causes embryonic lethality in mice[35,41]. We investigated the functions of Ndel[1] and Tara in cell movement. Our results reveal that Tara forms a functional complex with Ndel[1] and alters its intracellular distribution. We demonstrate that the Ndel1-Tara complex plays a role in regulating actin cytoskeleton organization, which is critical for cell migration

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Conclusion