Inheritance of the Golgi Apparatus and Cytokinesis Are Controlled by Degradation of GBF1

Magliozzi, Roberto; Carrero, Zunamys I.; Low, Teck Yew; Yuniati, Laurensia; Valdes-Quezada, Christian; Kruiswijk, Flore; Wijk, Koen van; Heck, Albert J. R.; Jackson, Catherine; Guardavaccaro, Daniele

doi:10.1016/j.celrep.2018.05.031

Cited by 13 publications

(22 citation statements)

References 32 publications

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“…It is interesting to note that during mitosis, when both the mitochondrial network and the Golgi apparatus undergo dramatic structural changes 41 , GBF1 activity is inhibited through phosphorylation by AMPK 42 . Therefore, given that GBF1 has a known role in mitosis 43 , another attractive hypothesis to investigate is whether GBF1 might coordinate the reorganization of the Golgi apparatus and the mitochondrial network during cell division.…”

Section: Discussionmentioning

confidence: 99%

GBF1 and Arf1 interact with Miro and regulate mitochondrial positioning within cells

Walch

Pellier

Leng

et al. 2018

Sci Rep

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The spatial organization of cells depends on coordination between cytoskeletal systems and intracellular organelles. The Arf1 small G protein and its activator GBF1 are important regulators of Golgi organization, maintaining its morphology and function. Here we show that GBF1 and its substrate Arf1 regulate the spatial organization of mitochondria in a microtubule-dependent manner. Miro is a mitochondrial membrane protein that interacts through adaptors with microtubule motor proteins such as cytoplasmic dynein, the major microtubule minus end directed motor. We demonstrate a physical interaction between GBF1 and Miro, and also between the active GTP-bound form of Arf1 and Miro. Inhibition of GBF1, inhibition of Arf1 activation, or overexpression of Miro, caused a collapse of the mitochondrial network towards the centrosome. The change in mitochondrial morphology upon GBF1 inhibition was due to a two-fold increase in the time engaged in retrograde movement compared to control conditions. Electron tomography revealed that GBF1 inhibition also resulted in larger mitochondria with more complex morphology. Miro silencing or drug inhibition of cytoplasmic dynein activity blocked the GBF1-dependent repositioning of mitochondria. Our results show that blocking GBF1 function promotes dynein- and Miro-dependent retrograde mitochondrial transport along microtubules towards the microtubule-organizing center, where they form an interconnected network.

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Section: Discussionmentioning

confidence: 99%

GBF1 and Arf1 interact with Miro and regulate mitochondrial positioning within cells

Walch

Pellier

Leng

et al. 2018

Sci Rep

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“…Reduced GBF1 levels in cultured cells have been associated with loss of GA integrity, COPI dispersal, compromise of the intracellular traffic, and cell death. 32 , 52 , 53 Nevertheless, it is important to highlight that tight regulation of GBF1 degradation is necessary for the physiological processes of post-mitotic GA re-assembly and cytokinesis completion. 54 Moreover, GBF1 regulates mitochondrial dynamics because the blocking of GBF1 activity leads to defects in mitochondrial morphology, positioning, and migration.…”

Section: Main Textmentioning

confidence: 99%

“…A zebrafish mutant line ( tsu3994 ) carrying the loss-of-function Gbf1 mutation Leu1246Arg in the HSD2 domain of the protein exhibits vascular collapse and prominent intracerebral and trunk hemorrhage. 53 …”

Section: Main Textmentioning

confidence: 99%

“…Given the important role of GBF1 in GA function and maintenance, and further considering that GBF1 depletion or inhibition has been linked with GA vesiculation and fragmentation, 32 , 52 , 53 , 56 we focused our functional analyses ascertaining the effect of GBF1 mutations on GA organization by using primary fibroblast cells established from skin biopsies. We were able to establish fibroblast cell lines from all the probands belonging to the four unrelated families reported in this study.…”

Section: Main Textmentioning

confidence: 99%

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De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation

Mendoza-Ferreira

Karakaya

Cengiz

et al. 2020

The American Journal of Human Genetics

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Distal hereditary motor neuropathies (HMNs) and axonal Charcot-Marie-Tooth neuropathy (CMT2) are clinically and genetically heterogeneous diseases characterized primarily by motor neuron degeneration and distal weakness. The genetic cause for about half of the individuals affected by HMN/CMT2 remains unknown. Here, we report the identification of pathogenic variants in GBF1 (Golgi brefeldin A-resistant guanine nucleotide exchange factor 1) in four unrelated families with individuals affected by sporadic or dominant HMN/CMT2. Genomic sequencing analyses in seven affected individuals uncovered four distinct heterozygous GBF1 variants, two of which occurred de novo . Other known HMN/CMT2-implicated genes were excluded. Affected individuals show HMN/CMT2 with slowly progressive distal muscle weakness and musculoskeletal deformities. Electrophysiological studies confirmed axonal damage with chronic neurogenic changes. Three individuals had additional distal sensory loss. GBF1 encodes a guanine-nucleotide exchange factor that facilitates the activation of members of the ARF (ADP-ribosylation factor) family of small GTPases. GBF1 is mainly involved in the formation of coatomer protein complex (COPI) vesicles, maintenance and function of the Golgi apparatus, and mitochondria migration and positioning. We demonstrate that GBF1 is present in mouse spinal cord and muscle tissues and is particularly abundant in neuropathologically relevant sites, such as the motor neuron and the growth cone. Consistent with the described role of GBF1 in Golgi function and maintenance, we observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals in this study. Our results not only reinforce the existing link between Golgi fragmentation and neurodegeneration but also demonstrate that pathogenic variants in GBF1 are associated with HMN/CMT2.

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“…has a special role at the cleavage furrow or if its requirement in cytokinesis reflects a need for normal Golgi function for proper cytokinesis (78,79). Giansanti and colleagues hypothesize a role for altered cytokinesis in promoting cancer (76).…”

Section: Mechanisms Of Oncogenesis By the Golph3 Complexmentioning

confidence: 99%

GOLPH3: a Golgi phosphatidylinositol(4)phosphate effector that directs vesicle trafficking and drives cancer

Kuna

Field

2019

Journal of Lipid Research

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ROLE OF THE PTDINS(4)P/GOLPH3 COMPLEX IN GOLGI FORWARD TRAFFICKING GOLPH3 (also known as GMx33 and GPP34) was first discovered by proteomic studies of purified Golgi fractions (6, 7). Further investigation revealed GOLPH3 to be a peripheral membrane protein, highly localized to the trans-Golgi and to vesicles budding from the trans-Golgi (6-8). The yeast ortholog of GOLPH3, VPS74, was also found to function at the Golgi (9, 10). However, the mechanism of localization to the Golgi and the purpose of GOLPH3 at the Golgi remained uncertain. During a genome-wide, proteomic screen for phosphoinositide binding proteins, we identified GOLPH3 as a protein that binds tightly and specifically to PtdIns(4)P (see Fig. 1) (11). We found that GOLPH3 binding to PtdIns(4)P is responsible for its localization to the Golgi in yeast and mammalian cells (11). GOLPH3 is a highly abundant (10 6 molecules per cell), ubiquitously expressed protein (11, 12). Thus, it is a major effector of PtdIns(4)P at the Golgi. PtdIns(4)P was already well known to be highly enriched at the trans-Golgi (13-15). From yeast to humans, PtdIns(4) P at the Golgi is required for Golgi-to-plasma membrane trafficking (16-19). Certainly, many effectors of PtdIns(4) P besides GOLPH3 have been described. These have a variety of activities, including several that function as nonvesicular lipid transporters, and have been the subject of many previous reviews (20-22). Two phosphatidylinositol-4-kinases (PI-4-kinases), PI4KII and PI4KIII, localize to the Golgi to produce PtdIns(4)P (13, 14, 23). Currently, we lack a detailed understanding of the differential roles for Abstract GOLPH3 is a peripheral membrane protein localized to the Golgi and its vesicles, but its purpose had been unclear. We found that GOLPH3 binds specifically to the phosphoinositide phosphatidylinositol(4)phosphate [PtdIns(4) P], which functions at the Golgi to promote vesicle exit for trafficking to the plasma membrane. PtdIns(4)P is enriched at the trans-Golgi and so recruits GOLPH3. Here, a GOLPH3 complex is formed when it binds to myosin18A (MYO18A), which binds F-actin. This complex generates a pulling force to extract vesicles from the Golgi; interference with this GOLPH3 complex results in dramatically reduced vesicle trafficking. The GOLPH3 complex has been identified as a driver of cancer in humans, likely through multiple mechanisms that activate secretory trafficking. In this review, we summarize the literature that identifies the nature of the GOLPH3 complex and its role in cancer. We also consider the GOLPH3 complex as a hub with the potential to reveal regulation of the Golgi and suggest the possibility of GOLPH3 complex inhibition as a therapeutic approach in cancer.-Kuna, R. S., and S. J. Field. GOLPH3: a Golgi phosphatidylinositol(4)phosphate effector that directs vesicle trafficking and drives cancer.

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Inheritance of the Golgi Apparatus and Cytokinesis Are Controlled by Degradation of GBF1

Cited by 13 publications

References 32 publications

GBF1 and Arf1 interact with Miro and regulate mitochondrial positioning within cells

GBF1 and Arf1 interact with Miro and regulate mitochondrial positioning within cells

De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation

GOLPH3: a Golgi phosphatidylinositol(4)phosphate effector that directs vesicle trafficking and drives cancer

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