PI3K regulates endocytosis after insulin secretion by mediating signaling crosstalk between Arf6 and Rab27a

Yamaoka, Mami; Ando, Tomomi; Terabayashi, Takeshi; Okamoto, Mitsuhiro; Takei, Masahiro; Nishioka, Tomoki; Kaibuchi, Kozo; Matsunaga, Kohichi; Ishizaki, Ray; Izumi, Tetsuro; Niki, Ichiro; Ishizaki, Toshimasa; Kimura, Toshihide

doi:10.1242/jcs.180141

Cited by 25 publications

(25 citation statements)

References 59 publications

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“…Furthermore, in the presence of glucose, ARNO binds the GAP for Rab27a, the latter being involved in exocytosis. This intricate crosstalk between phosphatidylinositol phosphate (PIP), ARFs and Rabs responds at least partially to cellular demands of endocytosis and exocytosis [ 112 ].…”

Section: The Endomembrane System Is Formed By Compartments Of Uniqmentioning

confidence: 99%

Recycling Endosomes and Viral Infection

Vale-Costa

Amorim

2016

Viruses

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Many viruses exploit specific arms of the endomembrane system. The unique composition of each arm prompts the development of remarkably specific interactions between viruses and sub-organelles. This review focuses on the viral–host interactions occurring on the endocytic recycling compartment (ERC), and mediated by its regulatory Ras-related in brain (Rab) GTPase Rab11. This protein regulates trafficking from the ERC and the trans-Golgi network to the plasma membrane. Such transport comprises intricate networks of proteins/lipids operating sequentially from the membrane of origin up to the cell surface. Rab11 is also emerging as a critical factor in an increasing number of infections by major animal viruses, including pathogens that provoke human disease. Understanding the interplay between the ERC and viruses is a milestone in human health. Rab11 has been associated with several steps of the viral lifecycles by unclear processes that use sophisticated diversified host machinery. For this reason, we first explore the state-of-the-art on processes regulating membrane composition and trafficking. Subsequently, this review outlines viral interactions with the ERC, highlighting current knowledge on viral-host binding partners. Finally, using examples from the few mechanistic studies available we emphasize how ERC functions are adjusted during infection to remodel cytoskeleton dynamics, innate immunity and membrane composition.

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Section: The Endomembrane System Is Formed By Compartments Of Uniqmentioning

confidence: 99%

Recycling Endosomes and Viral Infection

Vale-Costa

Amorim

2016

Viruses

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“…The IP pathway (Fig 1) plays important roles in regulating essential biological processes from yeast to humans, including mRNA transport from the nucleus to the cytoplasm (Wickramasinghe, et al, 2013), transcriptional regulation (Millard, et al, 2013; Steger, et al, 2003), embryogenesis (Seeds, et al, 2015), endocytosis (Yamaoka, et al, 2015), and ciliary function and signal transduction (Chavez, et al, 2015). We recently showed that this pathway controls transcription and allelic exclusion of variant surface glycoprotein (VSG) genes in T. brucei (Cestari and Stuart, 2015), allowing T. brucei to evade the host immune response.…”

Section: Introductionmentioning

confidence: 99%

Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites

Cestari

Haas

Moretti

et al. 2016

Cell Chemical Biology

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SUMMARY Kinetoplastids cause Chagas disease, Human African Trypanosomiasis (HAT) and leishmaniases. Current treatments for these diseases are toxic and inefficient, and our limited knowledge of drug targets and inhibitors has dramatically hindered the development of new drugs. Here we used a chemogenetic approach to identify new kinetoplastid drug targets and inhibitors. We conditionally knocked down Trypanosoma brucei inositol phosphate (IP) pathway genes and showed that almost every pathway step is essential for parasite growth and infection. Using a genetic and chemical screen we identified inhibitors that target IP pathway enzymes and are selective against T. brucei. Two series of these inhibitors acted on T. brucei inositol polyphosphate multikinase (IPMK) preventing Ins(1,3,4)P3 and Ins(1,3,4,5)P4 phosphorylation. We show that IPMK is functionally conserved among kinetoplastids and its inhibition is also lethal for Trypanosoma cruzi. Hence, IP enzymes are viable drug targets in kinetoplastids and IPMK inhibitors may aid the development of new drugs.

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“…Rab27s regulate endocytosis in exocytic pancreatic cell lines via its interaction with coronin 3(Kimura et al, 2008; Yamaoka et al, 2016), an actin-bundling protein that supports invagination for clathrin-dependent and clathrin-independent endocytosis(Mooren et al, 2012). Our data suggests that Rab27 isoforms regulates the endocytosis of larger molecular weight αsyn species in neurons.…”

Section: Discussionmentioning

confidence: 99%

Rab27 GTPases regulate alpha-synuclein uptake, cell-to-cell transmission, and toxicity

Underwood

Wang

Pathak

et al. 2020

Preprint

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SUMMARYParkinson’s disease and Dementia with Lewy Bodies are two common neurodegenerative disorders marked by proteinaceous aggregates composed primarily of the protein α-synuclein. α-Synuclein is hypothesized to have prion-like properties, by which misfolded α-synuclein induces the pathological aggregation of endogenous α-synuclein and neuronal loss. Rab27a and Rab27b are two highly homologous Rab GTPases that regulate α-synuclein secretion, clearance, and toxicity in vitro. In this study, we tested the impact of Rab27a/b on the transmission of pathogenic α-synuclein. Double knockout of both Rab27 isoforms eliminated α-synuclein aggregation and neuronal toxicity in primary cultured neurons exposed to fibrillary α-synuclein. In vivo, Rab27 double knockout mice lacked fibril-induced α-synuclein inclusions, dopaminergic neuron loss, and behavioral deficits seen in wildtype mice with fibril-induced inclusions. Studies using AlexaFluor488-labeled α-synuclein fibrils revealed that Rab27a/b knockout prevented α-synuclein internalization without affecting bulk endocytosis. Rab27a/b knockout also blocked the cell-to-cell spread of α-synuclein pathology in multifluidic, multichambered devices. This study provides critical insight into the role of Rab GTPases in Parkinson’s disease and identifies Rab27s as key players in the progression of synucleinopathies.

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PI3K regulates endocytosis after insulin secretion by mediating signaling crosstalk between Arf6 and Rab27a

Cited by 25 publications

References 59 publications

Recycling Endosomes and Viral Infection

Recycling Endosomes and Viral Infection

Chemogenetic Characterization of Inositol Phosphate Metabolic Pathway Reveals Druggable Enzymes for Targeting Kinetoplastid Parasites

Rab27 GTPases regulate alpha-synuclein uptake, cell-to-cell transmission, and toxicity

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