Rab6 Regulates Both ZW10/RINT-1– and Conserved Oligomeric Golgi Complex-dependent Golgi Trafficking and Homeostasis

Sun, Yi; Shestakova, Anna; Hunt, Lauren; Sehgal, Siddharth; Lupashin, Vladimir; Storrie, Brian

doi:10.1091/mbc.e07-01-0080

Cited by 84 publications

(159 citation statements)

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“…Several studies demonstrated that RINT1 is involved in ER-Golgi trafficking in vitro. 16,17,[19][20][21] Lin et al 19 associated the observed mitotic defects with Golgi dispersion and centrosome amplification. We demonstrated that centrosome amplification in MEFs is not correlated with mitotic defects and in NSC is not detected at all.…”

Section: Resultsmentioning

confidence: 99%

“…16,58 RINT1 was shown to be also involved in the more specific Rab6-dependent recycling pathway from the Golgi to the ER. 20 Disruption of the balance of the bi-directional ER/Golgi transport was shown to trigger Golgi fragmentation followed by ER stress. 1,55 Complementary to former RINT1 studies where ER stress was not reported 16,17,19 here we postulate that in our model, Rint1 deficiency generates ER/Golgi imbalance leading to Golgi apparatus fragmentation, induction of ER stress and ultimately cell death.…”

Section: Discussionmentioning

confidence: 99%

“…13 RINT1 was identified as a Rad50-interacting protein involved in G2/M checkpoint 14 and was shown to be involved in telomerase independent maintenance of telomeres via the interaction with p130. 15 The importance of RINT1 in Golgi-ER trafficking and thus in homeostasis of Cisand Trans-Golgi was demonstrated in vitro [16][17][18][19][20][21] where in vivo studies were limited by the early embryonic lethality (E5.5) associated with Rint1 inactivation. 19 Rint1 was proposed to be a tumor suppressor gene since its heterozygous mutation predisposed to tumor, 19 but it was also reported to act like an oncogene in glioblastomas.…”

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Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

et al. 2015

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Endoplasmic reticulum (ER) stress, defective autophagy and genomic instability in the central nervous system are often associated with severe developmental defects and neurodegeneration. Here, we reveal the role played by Rint1 in these different biological pathways to ensure normal development of the central nervous system and to prevent neurodegeneration. We found that inactivation of Rint1 in neuroprogenitors led to death at birth. Depletion of Rint1 caused genomic instability due to chromosome fusion in dividing cells. Furthermore, Rint1 deletion in developing brain promotes the disruption of ER and Cis/Trans Golgi homeostasis in neurons, followed by ER-stress increase. Interestingly, Rint1 deficiency was also associated with the inhibition of the autophagosome clearance. Altogether, our findings highlight the crucial roles of Rint1 in vivo in genomic stability maintenance, as well as in prevention of ER stress and autophagy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

et al. 2015

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“…S1B). Another dynein regulator, ZW10, is also required to maintain the structure of the Golgi complex (Hirose et al, 2004;Sun et al, 2007). In cells depleted of ZW10, the Golgi complex fragmented into very short tubules that remained in a patch close to the cell centre (supplementary material Fig.…”

Section: Both Nde1 and Ndel1 Are Important For Maintaining Organelle mentioning

confidence: 99%

Functional interplay between LIS1, NDE1 and NDEL1 in dynein-dependent organelle positioning

Lam

Vergnolle

Thorpe

et al. 2010

Journal of Cell Science

112

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Cytoplasmic dynein 1 is a minus-end-directed microtubule motor that is required for a wide range of activities involving movement or anchoring of cellular structures (Vallee et al., 2004). These activities include separation of chromosomes during mitosis, cell migration, and the movement and localisation of substrates such as mRNAs, signalling complexes and membrane organelles. To understand how dynein function over such a diverse range of activities is regulated, much attention has focussed on the composition of the dynein motor complex and the roles of accessory proteins.Dynein can be purified as a 1.6 MDa complex. This contains two copies of a motor subunit (dynein heavy chain; DHC), each of which comprises an AAA ATPase region involved in force generation and a stem region that connects the ATPase to the remaining, regulatory and cargo-binding subunits of the dynein complex. These subunits include dynein intermediate chain (DIC), dynein light intermediate chain (DLIC), and dynein light chains (DLCs) (Pfister et al., 2006). Dynein engages several accessory proteins or protein complexes, which might regulate its motor and/or cargo-binding activities. The best characterised of these is dynactin, a multiprotein complex that is almost universally associated with dynein-dependent functions (Schroer, 2004). More recently, several additional dynein-interacting proteins have been identified using a screen for Aspergillus nidulans mutants that are defective for nuclear distribution. These include NudF (Xiang et al., 1995) and NudE (Efimov and Morris, 2000), the higher eukaryote counterparts of which are Lissencephaly1 (LIS1) and NDE1, respectively. An NDE1-related protein, NDEL1 (also referred to as NudEL) has also been identified Sasaki et al., 2000). LIS1 interacts directly with DHC via sites on the first AAA domain and the stem region (Sasaki et al., 2000;Tai et al., 2002), with DIC (Tai et al., 2002), and with the p50 subunit of dynactin (Tai et al., 2002). NDEL1 and NDE1 also bind to dynein. However, the mode of binding might not be conserved here, because NDEL1 has been reported to bind HC (Sasaki et al., 2000), whereas NDE1 binds to DIC and the LC8 isoform of DLC (Stehman et al., 2007). In addition, NDE1 (Efimov and Morris, 2000;Feng et al., 2000) and NDEL1 (Derewenda et al., 2007;Niethammer et al., 2000;Sasaki et al., 2000) bind to LIS1 directly, and to each other (Bradshaw et al., 2009). There are currently two models to explain how these effectors modulate dynein function. They might regulate dynein motor activity directly (Mesngon et al., 2006;Yamada et al., 2008), or they might have a role in targeting dynein to cargoes (Liang et al., 2007;Vergnolle and Taylor, 2007).LIS1, NDE1 and NDEL1 have been implicated in many dyneinmediated activities, including cell migration, (Ding et al., 2009;Dujardin et al., 2003;Feng and Walsh, 2004;Kholmanskikh et al., 2003;Sasaki et al., 2005;Shu et al., 2004;Tanaka et al., 2004;Tsai et al., 2007;Tsai et al., 2005) , 2008). Mutations in or haplo-insufficiency of mammalian...

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“…To test this idea, we focused attention on the distribution of ERGIC-53. ERGIC-53 principally cycles between the ERGIC and ER in a COPI-dependent, but Rab6-independent manner (Girod et al, 1999;Nufer et al, 2002;Sun et al, 2007;White et al, 1999), thereby this protein is a good marker for the recycling pathway, although its loss does not block COPII assembly at ER exit sites (Mitrovik et al, 2008).Although the overall staining intensity of ERGIC-53 was substantially increased in syntaxin-18-depleted cells (Fig. 5A, left column), this was not due to its upregulation, as demonstrated by immunoblotting (supplementary material Fig.…”

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Role of syntaxin 18 in the organization of endoplasmic reticulum subdomains

Iinuma

Aoki

Arasaki

et al. 2009

Journal of Cell Science

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In Syn18(390)-transfected cells, we frequently (40-50% of cells at 72 hours after transfection) observed large patches positive for an ER membrane protein, Bap31 (Annaert et al., 1997) (Fig. 1B, middle row, left). Albeit much less frequently, similar patches were observed in cells transfected with the less efficient siRNA Syn18(770) (bottom row, left), suggesting that the redistribution of Bap31 is a consequence of syntaxin 18 depletion, and not a consequence of off target effect of Syn18(390). The different frequencies of the Bap31-positive patches are probably the result of the different knockdown efficiency of the two siRNAs. Fig. 1B also shows that silencing of syntaxin 18 causes a substantial dispersion of the Golgi complex marked by a cis-Golgi marker, p115 (Waters et al., 1992), without affecting microtubules. Other Golgi proteins, such as GM130, mannosidase II (Man II), β-COP and the KDEL receptor (KDEL-R), were also dispersed (supplementary material Fig. S1). The time course of morphological changes of the ER and Golgi structures concomitant with syntaxin 18 depletion is shown in supplementary material Fig. S2.To investigate in detail the morphology of the ER and the Golgi complex in syntaxin-18-depleted cells, we performed electron microscopy. In Syn18(390)-transfected cells, vesiculated membrane structures, instead of the Golgi stacks, were observed at the perinuclear region ( Fig. 2B,C; supplementary material Fig. S3). Furthermore, there were well-defined membrane aggregates consisting of a convoluted network of branching tubules, as well as dilated ER structures, in Syn18(390)-transfected cells ( Fig. 2B-D; supplementary material Fig. S3). Similar results were obtained with Syn18(770)-transfected cells, although ER aggregates were observed only in some cells (data not shown). Quantitative analysis showed that the area and length of the ER normalized to the cytoplasmic area of Syn18(390)-transfected cells are higher than those of mock-transfected cells (Tables 1 and 2), suggesting a proliferation of the ER membrane concomitant with syntaxin 18 depletion.Immunoelectron microscopy confirmed Golgi disassembly and the formation of ER membrane aggregates in syntaxin-18-depleted cells. In Syn18(390)-transfected cells, a cis-Golgi marker, p115, and . At 72 hours after transfection, the cells were stained with an antibody against syntaxin 18 (right) or solubilized in phosphate-buffered saline with 0.5% SDS. The lysates (10 μg each) were separated by SDS-PAGE and analyzed by immunoblotting with the indicated antibodies (left). (B) HeLa cells were treated as described in A and stained for Bap31, p115 or α-tubulin. The distributions of the proteins investigated were indistinguishable between mock-transfected cells and lamin A/C siRNA-treated cells (data not shown). Scale bars: 10 μm. The boxed area in B is shown enlarged in C. G, Golgi complex; M, mitochondria; ER, endoplasmic reticulum; N, nucleus. Arrows, arrowheads and asterisks indicate vesiculated membrane structures, ER patches and dilated ER, respectiv...

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Rab6 Regulates Both ZW10/RINT-1– and Conserved Oligomeric Golgi Complex-dependent Golgi Trafficking and Homeostasis

Cited by 84 publications

References 53 publications

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain

Functional interplay between LIS1, NDE1 and NDEL1 in dynein-dependent organelle positioning

Role of syntaxin 18 in the organization of endoplasmic reticulum subdomains

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