Developmentally regulated GTP-binding protein 2 is required for stabilization of Rac1-positive membrane tubules

Mani, Muralidharan; Lee, Unn Hwa; Yoon, Nal Ae; Yoon, Eun Hye; Lee, Byung Ju; Cho, Wha Ja; Park, Jeong Woo

doi:10.1016/j.bbrc.2017.08.110

Cited by 6 publications

(6 citation statements)

References 25 publications

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“…How PtdIns4P might facilitate tubule stability or extension is not entirely clear, but most likely PtdIns4P serves as a platform to recruit membrane bending proteins (Kitamata et al, 2020). These may include BLOC-1 itself [ (Jani et al, 2021); see below] and/or other PtdIns4P-binding proteins such as EHD1 or DRG2 (Jovic et al, 2009;Ma et al, 2020;Mani et al, 2017). Alternatively, PtdIns4P might be required to concentrate KIF13A either indirectly via clustering its adaptor AP-1 (Wang et al, 2003) or directly, consistent with the role of PtdIns(4,5)P2 in clustering KIF1A and KIF5B to drive membrane transport and tubulation (Du et al, 2016;Klopfenstein et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Two type II phosphatidylinositol 4-kinases function sequentially in tubule-mediated cargo delivery from early endosomes to melanosomes

Zhu

Jaume

et al. 2021

Preprint

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Melanosomes are pigment cell-specific lysosome-related organelles in which melanin pigments are synthesized and stored. Melanosome maturation requires delivery of melanogenic cargoes via tubular transport carriers that emanate from early endosomes and that require BLOC-1 for their formation. Here we show that phosphatidylinositol-4-phosphate (PtdIns4P) and the type II PtdIns-4-kinases (PI4KIIα and PI4KIIβ) support BLOC-1-dependent tubule formation to regulate melanosome biogenesis. Depletion of PI4KIIα or PI4KIIβ with shRNAs in melanocytes reduced melanin content and misrouted BLOC-1-dependent cargoes to late endosomes/lysosomes. Genetic epistasis, cell fractionation, and quantitative live-cell imaging analyses show that PI4KIIα and PI4KIIβ function sequentially and non-redundantly downstream of BLOC-1 during tubule elongation towards melanosomes by generating local pools of PtdIns4P. The data demonstrate that both type II PtdIns-4-kinases are necessary for efficient BLOC-1-dependent tubule elongation and subsequent melanosome contact and content delivery during melanosome biogenesis. The independent functions of PtdIns-4-kinases in tubule extension are likely downstream of redundant functions in BLOC-1-dependent tubule initiation.SUMMARYContents are delivered from early endosomal intermediates to maturing melanosomes through tubular transport carriers. Zhu et al show that two type II phosphatidylinositol kinases, PI4KIIα and PI4KIIβ, sequentially generate phosphatidylinositol-4-phosphate during tubule initiation and elongation for ultimate melanosome content delivery.

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Section: Discussionmentioning

confidence: 99%

Two type II phosphatidylinositol 4-kinases function sequentially in tubule-mediated cargo delivery from early endosomes to melanosomes

Zhu

Jaume

et al. 2021

Preprint

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“…Rab5 is implicated in ciliary endomembrane processes at or near the ciliary base ( Blacque et al, 2018 ). Also, Drg2 appears to regulate membrane tubulin stability cooperatively with Rac1 in mammalian cells ( Mani et al, 2017 ). However, our Drg2 MO results (Fig.…”

Section: Discussionmentioning

confidence: 99%

Developmentally regulated GTP-binding protein 1 modulates ciliogenesis via an interaction with Dishevelled

Lee

Hwang

Yoon

et al. 2019

Journal of Cell Biology

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Cilia are critical for proper embryonic development and maintaining homeostasis. Although extensively studied, there are still significant gaps regarding the proteins involved in regulating ciliogenesis. Using the Xenopus laevis embryo, we show that Dishevelled (Dvl), a key Wnt signaling scaffold that is critical to proper ciliogenesis, interacts with Drg1 (developmentally regulated GTP-binding protein 1). The loss of Drg1 or disruption of the interaction with Dvl reduces the length and number of cilia and displays defects in basal body migration and docking to the apical surface of multiciliated cells (MCCs). Moreover, Drg1 morphants display abnormal rotational polarity of basal bodies and a decrease in apical actin and RhoA activity that can be attributed to disruption of the protein complex between Dvl and Daam1, as well as between Daam1 and RhoA. These results support the concept that the Drg1–Dvl interaction regulates apical actin polymerization and stability in MCCs. Thus, Drg1 is a newly identified partner of Dvl in regulating ciliogenesis.

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“…Similar to its role in endosomes, DRG2 is also involved in the regulation of membrane tubules [ 83 ]. Membrane tubules are formed as part of intracellular organelles such as the Golgi and endoplasmic reticulum.…”

Section: Structure Biochemistry and Regulation Of Drgsmentioning

confidence: 99%

“…Membrane tubules are formed as part of intracellular organelles such as the Golgi and endoplasmic reticulum. DRG2 was shown to be capable of localizing to membrane tubules where it interacts with GTP bound Rac1 [ 83 ]. Depletion of DRG2 caused a decrease in the length of Rac1 membrane tubules suggesting DRG2 is required for the stabilization of these structures [ 83 ].…”

Section: Structure Biochemistry and Regulation Of Drgsmentioning

confidence: 99%

Developmentally regulated GTPases: structure, function and roles in disease

Westrip

Zhuang

Hall

et al. 2021

Cell. Mol. Life Sci.

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GTPases are a large superfamily of evolutionarily conserved proteins involved in a variety of fundamental cellular processes. The developmentally regulated GTP-binding protein (DRG) subfamily of GTPases consists of two highly conserved paralogs, DRG1 and DRG2, both of which have been implicated in the regulation of cell proliferation, translation and microtubules. Furthermore, DRG1 and 2 proteins both have a conserved binding partner, DRG family regulatory protein 1 and 2 (DFRP1 and DFRP2), respectively, that prevents them from being degraded. Similar to DRGs, the DFRP proteins have also been studied in the context of cell growth control and translation. Despite these proteins having been implicated in several fundamental cellular processes they remain relatively poorly characterized, however. In this review, we provide an overview of the structural biology and biochemistry of DRG GTPases and discuss current understanding of DRGs and DFRPs in normal physiology, as well as their emerging roles in diseases such as cancer.

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Developmentally regulated GTP-binding protein 2 is required for stabilization of Rac1-positive membrane tubules

Cited by 6 publications

References 25 publications

Two type II phosphatidylinositol 4-kinases function sequentially in tubule-mediated cargo delivery from early endosomes to melanosomes

Two type II phosphatidylinositol 4-kinases function sequentially in tubule-mediated cargo delivery from early endosomes to melanosomes

Developmentally regulated GTP-binding protein 1 modulates ciliogenesis via an interaction with Dishevelled

Developmentally regulated GTPases: structure, function and roles in disease

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