Characterization of RIN3 as a Guanine Nucleotide Exchange Factor for the Rab5 Subfamily GTPase Rab31

Kajiho, Hiroaki; Sakurai, Kyoko; Minoda, Tomohiro; Yoshikawa, Manabu; Nakagawa, Satoshi; Fukushima, Seigo; Kontani, Kenji; Katada, Toshiaki

doi:10.1074/jbc.m110.172445

Cited by 50 publications

(52 citation statements)

References 49 publications

(27 reference statements)

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“…4a, left panel ). The former is involved in microglial endocytosis and interacts with BIN1 and CD2AP , suggesting possible involvement in APP trafficking 46, 47 . The latter is a potent vasoconstrictor in cerebral circulation, which has been linked to ischemic stroke 48 .…”

Section: Resultsmentioning

confidence: 99%

A single cell brain atlas in human Alzheimer’s disease

Grubman

Chew

Ouyang

et al. 2019

Preprint

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26Alzheimer's disease (AD) is a heterogeneous disease that is largely dependent on the complex 27 cellular microenvironment in the brain. This complexity impedes our understanding of how 28 individual cell types contribute to disease progression and outcome. To characterize the 29 molecular and functional cell diversity in the human AD brain we utilized single nuclei RNA-30 seq in AD and control patient brains in order to map the landscape of cellular heterogeneity in 31 AD. We detail gene expression changes at the level of cells and cell subclusters, highlighting 32 specific cellular contributions to global gene expression patterns between control and 33 Alzheimer's patient brains. We observed distinct cellular regulation of APOE which was 34 repressed in oligodendrocyte progenitor cells (OPCs) and astrocyte AD subclusters, and highly 35 enriched in a microglial AD subcluster. In addition, oligodendrocyte and microglia AD 36 subclusters show discordant expression of APOE. Integration of transcription factor regulatory 37 modules with downstream GWAS gene targets revealed subcluster-specific control of AD cell 38 fate transitions. For example, this analysis uncovered that astrocyte diversity in AD was under 39 the control of transcription factor EB (TFEB), a master regulator of lysosomal function and 40 which initiated a regulatory cascade containing multiple AD GWAS genes. These results 41 establish functional links between specific cellular sub-populations in AD, and provide new 42 insights into the coordinated control of AD GWAS genes and their cell-type specific 43 contribution to disease susceptibility. Finally, we created an interactive reference web resource 44 which will facilitate brain and AD researchers to explore the molecular architecture of subtype 45 and AD-specific cell identity, molecular and functional diversity at the single cell level. 46Highlights 47 • We generated the first human single cell transcriptome in AD patient brains 48 • Our study unveiled 9 clusters of cell-type specific and common gene expression 49 patterns between control and AD brains, including clusters of genes that present 50 properties of different cell types (i.e. astrocytes and oligodendrocytes) 51 • Our analyses also uncovered functionally specialized sub-cellular clusters: 5 52 microglial clusters, 8 astrocyte clusters, 6 neuronal clusters, 6 oligodendrocyte 53 clusters, 4 OPC and 2 endothelial clusters, each enriched for specific ontological 54 gene categories 55 • Our analyses found manifold AD GWAS genes specifically associated with one 56 cell-type, and sets of AD GWAS genes co-ordinately and differentially regulated 57 between different brain cell-types in AD sub-cellular clusters 58 • We mapped the regulatory landscape driving transcriptional changes in AD brain, 59 and identified transcription factor networks which we predict to control cell fate 60 transitions between control and AD sub-cellular clusters 61 • Finally, we provide an interactive web-resource that allows the user to further 62 visua...

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Section: Resultsmentioning

confidence: 99%

A single cell brain atlas in human Alzheimer’s disease

Grubman

Chew

Ouyang

et al. 2019

Preprint

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“…A more recent study reported that the yeast Ypt1 (mammalian homolog Rab1) regulates macroautophagy by recruiting its effector, Atg1, to the preautophagosomal structure to tether Atg9 vesicles to each other or to other membranes [32]. Rab31, a Rab5 subfamily GTPase, is thought to be involved in membrane budding and the trafficking of early endosomes [33]. Rab5 was shown to participate in autophagosome formation and elimination of toxic mutant huntingtin in cell model of Huntington's disease [34].…”

Section: Discussionmentioning

confidence: 98%

miR-184 and miR-150 promote renal glomerular mesangial cell aging by targeting Rab1a and Rab31

Liu

Chen

et al. 2015

Experimental Cell Research

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“…another Rab5 GEF (108,109), has been identified in a large-scale genome-wide association study of AD (110). Recruitment of such effectors (19,111,112) to endosomes would increase the level of Rab5 on these organelles.…”

Section: 2mentioning

confidence: 99%

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Xu¹,

Weissmiller²,

White³

et al. 2016

Journal of Clinical Investigation

141

202

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R e s e a R c h a R t i c l e1 8 1 6jci.org Volume 126Number 5 May 2016 26, 54, 55). We assayed the level of GTP-Rab5 in brains of 12-monthold Ts65Dn and 2N mice following a published protocol (56). As previously reported (28), the level of full-length APP in Ts65Dn was approximately 1.5-fold than in 2N samples ( We next tested whether the increase in App gene dose in Ts65Dn BFCNs was responsible for enlargement of Rab5 + endosomes (Figure 1). By immunoblotting, the APP siRNA caused an approximately 30% reduction in the level of full-length APP, as compared with control siRNA ( Figure 2E). Rab5 + puncta in BFCNs treated with either the APP siRNA or control siRNA were analyzed (Figure 2, F and G) as in Figure 1. Large, sometimes lobulated Rab5 + puncta were seen in cultures treated with the control siRNA, whereas these structures were typically smaller and rounded in cultures treated with the APP siRNA ( Figure 2G). Treatment with the APP siRNA significantly reduced the size of Rab5 + puncta in Ts65Dn neurons to a value equivalent to that in 2N neurons ( Figure 2F). Thus, increased App gene dose is necessary for increased Rab5 activation and for early endosome enlargement in Ts65Dn neurons.Full-length APP and β-CTF caused enlargement of early endosomes in PC12 cells. To determine how increased APP expression caused an increase in Rab5 activation, we asked which APP product(s) were responsible (Supplemental Figure 1A). We transfected PC12M cells with full-length APP-GFP, C99-GFP (β-CTF), C83-GFP (α-CTF), or AICD-GFP and examined endosomes by live cell imaging (Supplemental Figure 1B). Bright foci of GFP + intracellular structures were present in PC12M cells that overexpressed APP-GFP or C99-GFP. In contrast, cells expressing C83-GFP or AICD-GFP showed diffuse, hazy signals for GFP, with occasional foci in C83-GFP cells. In APP-GFP and C99-GFP cells, the GFP + intracellular structures were, on average, approximately 2 μm 2 (Supplemental Figure 1E). GFP signals in C83-GFP or AICD-GFP cells contained speckled small puncta within the haze, as well as a small number of larger bright puncta, as seen in cells expressing C99-GFP and APP-GFP (Supplemental Figure 1B). However, the average puncta size in C83-GFP and AICD-GFP cells was approximately 1.2 and 1.3 μm 2 , respectively. Thus, overexpressing APP and β-CTF, but not α-CTF or AICD, routinely induced formation of enlarged, bright intracellular structures. We also tested two APP mutants: APP M596V and APP SWE . APP M596V , which abolishes β-secretase cleavage, prevents production of β-CTF (57); APP SWE enhances β-secretase cleavage to increase the level of β-CTF (57). Both induced the formation of enlarged intracellular structures (Supplemental Figure 1C).We examined colocalization of APP or C99 with Rab5 in cotransfection experiments; APP-mCherry with GFP-Rab5 WT ( Figure 3B); C99-GFP with mCherry-Rab5 WT ( Figure 3C); and Rab5 + endosomes (26, 28, 37) was correlated with reduced endosomal trafficking and signaling of nerve growth factor (NGF), leading to degeneration...

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Characterization of RIN3 as a Guanine Nucleotide Exchange Factor for the Rab5 Subfamily GTPase Rab31

Cited by 50 publications

References 49 publications

A single cell brain atlas in human Alzheimer’s disease

A single cell brain atlas in human Alzheimer’s disease

miR-184 and miR-150 promote renal glomerular mesangial cell aging by targeting Rab1a and Rab31

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

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