Role of small GTPases in polarized vesicle transport to primary cilium

Small guanosine triphosphatases (GTPases) of the Rab and Arf families are key regulators of vesicle formation and membrane trafficking. Membrane transport plays an important role in the central nervous system. In this regard, neurons require a constant flow of membranes for the correct distribution of receptors, for the precise composition of proteins and organelles in dendrites and axons, for the continuous exocytosis/endocytosis of synaptic vesicles and for the elimination of dysfunctional proteins. Thus, it is not surprising that Rab and Arf GTPases have been associated with neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Both pathologies share characteristics such as the presence of protein aggregates and/or the fragmentation of the Golgi apparatus, hallmarks that have been related to both Rab and Arf GTPases functions. Despite their relationship with neurodegenerative disorders, very few studies have focused on the role of these GTPases in the pathogenesis of neurodegeneration. In this review, we summarize their importance in the onset and progression of Alzheimer’s and Parkinson’s diseases, as well as their emergence as potential therapeutical targets for neurodegeneration.

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Protein farnesylation is upregulated in Alzheimer’s human brains and neuron-specific suppression of farnesyltransferase mitigates pathogenic processes in Alzheimer’s model mice

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01231-5 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Angela Jeong ◽

Shaowu Cheng ◽

Rui Zhong ◽

David A. Bennett ◽

Martin O. Bergö ◽

...

Keyword(s):

Cognitive Impairment ◽

Small Gtpases ◽

Specific Role ◽

Postmortem Brain ◽

Effective Prevention ◽

Postmortem Brain Tissue ◽

Mtorc1 Signaling ◽

Behavioral Assessments ◽

Human Brains

AbstractThe pathogenic mechanisms underlying the development of Alzheimer’s disease (AD) remain elusive and to date there are no effective prevention or treatment for AD. Farnesyltransferase (FT) catalyzes a key posttranslational modification process called farnesylation, in which the isoprenoid farnesyl pyrophosphate is attached to target proteins, facilitating their membrane localization and their interactions with downstream effectors. Farnesylated proteins, including the Ras superfamily of small GTPases, are involved in regulating diverse physiological and pathological processes. Emerging evidence suggests that isoprenoids and farnesylated proteins may play an important role in the pathogenesis of AD. However, the dynamics of FT and protein farnesylation in human brains and the specific role of neuronal FT in the pathogenic progression of AD are not known. Here, using postmortem brain tissue from individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimer’s dementia, we found that the levels of FT and membrane-associated H-Ras, an exclusively farnesylated protein, and its downstream effector ERK were markedly increased in AD and MCI compared with NCI. To elucidate the specific role of neuronal FT in AD pathogenesis, we generated the transgenic AD model APP/PS1 mice with forebrain neuron-specific FT knockout, followed by a battery of behavioral assessments, biochemical assays, and unbiased transcriptomic analysis. Our results showed that the neuronal FT deletion mitigates memory impairment and amyloid neuropathology in APP/PS1 mice through suppressing amyloid generation and reversing the pathogenic hyperactivation of mTORC1 signaling. These findings suggest that aberrant upregulation of protein farnesylation is an early driving force in the pathogenic cascade of AD and that targeting FT or its downstream signaling pathways presents a viable therapeutic strategy against AD.

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Suppressive Role of Bam32/DAPP1 in Chemokine-Induced Neutrophil Recruitment

International Journal of Molecular Sciences ◽

10.3390/ijms22041825 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1825

Author(s):

Li Hao ◽

Aaron J. Marshall ◽

Lixin Liu

Keyword(s):

Small Gtpases ◽

Neutrophil Recruitment ◽

Neutrophil Chemotaxis ◽

Wild Type ◽

Adaptor Molecule ◽

Geranylgeranyltransferase I ◽

And Migration ◽

Rap1 Activation

Bam32 (B cell adaptor molecule of 32 kDa) functions in the immune responses of various leukocytes. However, the role of neutrophil Bam32 in inflammation is entirely unknown. Here, we determined the role of Bam32 in chemokine CXCL2-induced neutrophil chemotaxis in three mouse models of neutrophil recruitment. By using intravital microscopy in the mouse cremaster muscle, we found that transmigrated neutrophil number, neutrophil chemotaxis velocity, and total neutrophil chemotaxis distance were increased in Bam32−/− mice when compared with wild-type (WT) mice. In CXCL2-induced mouse peritonitis, the total emigrated neutrophils were increased in Bam32−/− mice at 2 but not 4 h. The CXCL2-induced chemotaxis distance and migration velocity of isolated Bam32−/− neutrophils in vitro were increased. We examined the activation of small GTPases Rac1, Rac2, and Rap1; the levels of phospho-Akt2 and total Akt2; and their crosstalk with Bam32 in neutrophils. The deficiency of Bam32 suppressed Rap1 activation without changing the activation of Rac1 and Rac2. The pharmacological inhibition of Rap1 by geranylgeranyltransferase I inhibitor (GGTI298) increased WT neutrophil chemotaxis. In addition, the deficiency of Bam32, as well as the inhibition of Rap1 activation, increased the levels of CXCL2-induced Akt1/2 phosphorylation at Thr308/309 in neutrophils. The inhibition of Akt by SH-5 attenuated CXCL2-induced adhesion and emigration in Bam32−/− mice. Together, our results reveal that Bam32 has a suppressive role in chemokine-induced neutrophil chemotaxis by regulating Rap1 activation and that this role of Bam32 in chemokine-induced neutrophil recruitment relies on the activation of PI3K effector Akt.

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Cells in tight spaces: the role of cell shape in cell function

The Journal of Cell Biology ◽

10.1083/jcb.201009048 ◽

2010 ◽

Vol 191 (2) ◽

pp. 233-236 ◽

Cited By ~ 31

Author(s):

Jagesh V. Shah

Keyword(s):

Primary Cilium ◽

Cell Shape ◽

Cell Function ◽

Cellular Function ◽

Cell Geometry ◽

Intracellular Organization ◽

Cell Biol

In this issue, Pitaval et al. (2010. J. Cell Biol. doi:10.1083/jcb.201004003) demonstrate that cell geometry can regulate the elaboration of a primary cilium. Their findings and approaches are part of a historical line of inquiry investigating the role of cell shape in intracellular organization and cellular function.

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The Role of Motor Clustering in Kinesin-Driven Vesicle Transport

Biophysical Journal ◽

10.1016/j.bpj.2020.11.1171 ◽

2021 ◽

Vol 120 (3) ◽

pp. 164a

Author(s):

Rui Jiang ◽

Qingzhou Feng ◽

You Jung Kang ◽

William O. Hancock

Keyword(s):

Vesicle Transport

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Role of Rho small GTPases in meniscus cells

Journal of Orthopaedic Research® ◽

10.1002/jor.22703 ◽

2014 ◽

Vol 32 (11) ◽

pp. 1479-1486 ◽

Cited By ~ 4

Author(s):

Tomoko Kanazawa ◽

Takayuki Furumatsu ◽

Emi Matsumoto-Ogawa ◽

Ami Maehara ◽

Toshifumi Ozaki

Keyword(s):

Small Gtpases ◽

Meniscus Cells

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O-18: Role of the small GTPases Rab4 and Rab5 in insulin-induced glucose transport

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-0029-1211509 ◽

2009 ◽

Vol 104 (S 02) ◽

pp. 26-27

Author(s):

Mireille Cormont ◽

Marie-Noëlle Bortoluzzi ◽

Nadine Gautier ◽

Emmanuel Van Obberghen ◽

Yannick Le Marchand-Brustel

Keyword(s):

Glucose Transport ◽

Small Gtpases ◽

O 18

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Trafficking to the primary cilium membrane

Molecular Biology of the Cell ◽

10.1091/mbc.e16-07-0505 ◽

2017 ◽

Vol 28 (2) ◽

pp. 233-239 ◽

Cited By ~ 24

Author(s):

Saikat Mukhopadhyay ◽

Hemant B. Badgandi ◽

Sun-hee Hwang ◽

Bandarigoda Somatilaka ◽

Issei S. Shimada ◽

...

Keyword(s):

Membrane Proteins ◽

Signaling Pathways ◽

Primary Cilium ◽

Hedgehog Signaling ◽

Diffusion Barriers ◽

Disease Pathogenesis ◽

Ciliary Membrane ◽

Multiple Organs ◽

Sensory Reception

The primary cilium has been found to be associated with a number of cellular signaling pathways, such as vertebrate hedgehog signaling, and implicated in the pathogenesis of diseases affecting multiple organs, including the neural tube, kidney, and brain. The primary cilium is the site where a subset of the cell's membrane proteins is enriched. However, pathways that target and concentrate membrane proteins in cilia are not well understood. Processes determining the level of proteins in the ciliary membrane include entry into the compartment, removal, and retention by diffusion barriers such as the transition zone. Proteins that are concentrated in the ciliary membrane are also localized to other cellular sites. Thus it is critical to determine the particular role for ciliary compartmentalization in sensory reception and signaling pathways. Here we provide a brief overview of our current understanding of compartmentalization of proteins in the ciliary membrane and the dynamics of trafficking into and out of the cilium. We also discuss major unanswered questions regarding the role that defects in ciliary compartmentalization might play in disease pathogenesis. Understanding the trafficking mechanisms that underlie the role of ciliary compartmentalization in signaling might provide unique approaches for intervention in progressive ciliopathies.

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Two New Ypt GTPases Are Required for Exit From the Yeast trans-Golgi Compartment

The Journal of Cell Biology ◽

10.1083/jcb.137.3.563 ◽

1997 ◽

Vol 137 (3) ◽

pp. 563-580 ◽

Cited By ~ 151

Author(s):

Gregory Jedd ◽

Jon Mulholland ◽

Nava Segev

Keyword(s):

Protein Transport ◽

Small Gtpases ◽

Yeast Cells ◽

Secretory Vesicles ◽

Golgi Compartment ◽

Rab Family ◽

Vacuolar Protein ◽

Exocytic Pathway ◽

Mutant Cells

Small GTPases of the Ypt/rab family are involved in the regulation of vesicular transport. These GTPases apparently function during the targeting of vesicles to the acceptor compartment. Two members of the Ypt/rab family, Ypt1p and Sec4p, have been shown to regulate early and late steps of the yeast exocytic pathway, respectively. Here we tested the role of two newly identified GTPases, Ypt31p and Ypt32p. These two proteins share 81% identity and 90% similarity, and belong to the same protein subfamily as Ypt1p and Sec4p. Yeast cells can tolerate deletion of either the YPT31 or the YPT32 gene, but not both. These observations suggest that Ypt31p and Ypt32p perform identical or overlapping functions. Cells deleted for the YPT31 gene and carrying a conditional ypt32 mutation exhibit protein transport defects in the late exocytic pathway, but not in vacuolar protein sorting. The ypt31/ 32 mutant secretory defect is clearly downstream from that displayed by a ypt1 mutant and is similar to that of sec4 mutant cells. However, electron microscopy revealed that while sec4 mutant cells accumulate secretory vesicles, ypt31/32 mutant cells accumulate aberrant Golgi structures. The ypt31/32 phenotype is epistatic to that of a sec1 mutant, which accumulates secretory vesicles. Together, these results indicate that the Ypt31/32p GTPases are required for a step that occurs in the transGolgi compartment, between the reactions regulated by Ypt1p and Sec4p. This step might involve budding of vesicles from the trans-Golgi. Alternatively, Ypt31/ 32p might promote secretion indirectly, by allowing fusion of recycling vesicles with the trans-Golgi compartment.

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A Model for Primary Cilium Biogenesis by Polarized Epithelial Cells: Role of the Midbody Remnant and Associated Specialized Membranes

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.622918 ◽

2021 ◽

Vol 8 ◽

Author(s):

Leticia Labat-de-Hoz ◽

Armando Rubio-Ramos ◽

Javier Casares-Arias ◽

Miguel Bernabé-Rubio ◽

Isabel Correas ◽

...

Keyword(s):

Cell Surface ◽

Primary Cilium ◽

Primary Cilia ◽

Control Cell ◽

Future Research ◽

Alternative Route ◽

Ciliary Membrane ◽

Cilium Formation ◽

Membrane Compartmentalization

Primary cilia are solitary, microtubule-based protrusions surrounded by a ciliary membrane equipped with selected receptors that orchestrate important signaling pathways that control cell growth, differentiation, development and homeostasis. Depending on the cell type, primary cilium assembly takes place intracellularly or at the cell surface. The intracellular route has been the focus of research on primary cilium biogenesis, whereas the route that occurs at the cell surface, which we call the “alternative” route, has been much less thoroughly characterized. In this review, based on recent experimental evidence, we present a model of primary ciliogenesis by the alternative route in which the remnant of the midbody generated upon cytokinesis acquires compact membranes, that are involved in compartmentalization of biological membranes. The midbody remnant delivers part of those membranes to the centrosome in order to assemble the ciliary membrane, thereby licensing primary cilium formation. The midbody remnant's involvement in primary cilium formation, the regulation of its inheritance by the ESCRT machinery, and the assembly of the ciliary membrane from the membranes originally associated with the remnant are discussed in the context of the literature concerning the ciliary membrane, the emerging roles of the midbody remnant, the regulation of cytokinesis, and the role of membrane compartmentalization. We also present a model of cilium emergence during evolution, and summarize the directions for future research.

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