The Rab11-binding protein RELCH/KIAA1468 controls intracellular cholesterol distribution

Sobajima, Tomoaki; Yoshimura, Sho; Maeda, Tomomi; Miyata, Haruhiko; Miyoshi, Eiji; Harada, Akira

doi:10.1083/jcb.201709123

Cited by 47 publications

(53 citation statements)

References 52 publications

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“…Rab11A: Rab11 is conserved in most eukaryotes and participates in traffic through recycling endosomes and the trans Golgi network (Wandinger-Ness and Zerial, 2014). Amongst the top ~30 hits are thirteen known Rab11 effectors: the Rab8 GEF Rab3IP/Rabin8, the Rab GAP TBC1D12, the PI 4-kinase PI4KIIIβ, subunits of the exocyst complex, the A-kinase-anchoring protein D-AKAP2/AKAP10, the kinesins KIF13A/B, and the proteins of unknown function WDR44/Rab11BP and RELCH/KIAA1468 (Knödler et al, 2010;Sobajima et al, 2018;Longatti et al, 2012;Zeng et al, 1999;Eggers et al, 2009;Oguchi et al, 2017;Etoh and Fukuda, 2019) ( Figure 5A). In addition, the hits include two TBC domain GAPs reported to act on Rab11, EVI5 and RABGAP1 (Fuchs et al, 2007;Laflamme et al, 2012).…”

Section: Application Of Mitoid To a Panel Of Rab Gtpasesmentioning

confidence: 99%

“…OSBPL9 (ORP9) is a member of a family of cholesterol transfer proteins that binds to the protein VAP in the ER and to PtdIns(4)P on the Golgi and endosomes (Ngo and Ridgway, 2009;Dong et al, 2016). RELCH has recently been reported as a Rab11 effector and to have a role in cholesterol transport (Sobajima et al, 2018).…”

Section: Validation Of Novel Interaction Partners For Rab2a Rab5a Amentioning

confidence: 99%

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In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

Gillingham

Bertram

Begum

et al. 2019

Preprint

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The GTPases of the Ras superfamily regulate cell growth, membrane traffic and the cytoskeleton, and a wide range of diseases are caused by mutations in particular members. They function as switchable landmarks with the active GTP-bound form recruiting to the membrane a specific set of effector proteins. The GTPases are precisely controlled by regulators that promote acquisition of GTP (GEFs) or its hydrolysis to GDP (GAPs). We report here MitoID, a method for identifying effectors and regulators by performing in vivo proximity biotinylation with mitochondriallylocalized forms of the GTPases. Applying this to 11 human Rab GTPases identified many known effectors and GAPs, as well as putative novel effectors, with examples of the latter validated for Rab2, Rab5 and Rab9. MitoID can also efficiently identify effectors and GAPs of Rho and Ras family GTPases such as Cdc42, RhoA, Rheb, and N-Ras, and can identify GEFs by use of GDP-bound forms.

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Section: Application Of Mitoid To a Panel Of Rab Gtpasesmentioning

confidence: 99%

Section: Validation Of Novel Interaction Partners For Rab2a Rab5a Amentioning

confidence: 99%

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

Gillingham

Bertram

Begum

et al. 2019

Preprint

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“…Despite the extensive Golgi localization of OSBP in response to TPA treatment, there was only a 50% increase in SM synthesis (compared to >200% in response to 25OH) that was independent of OSBP expression. Thus, a PKD‐dependent mechanism could direct OSBP to the Golgi apparatus where it has an alternate function, such as Rab11‐dependent cholesterol export from recycling endosomes or endosome‐ER tethering involved in retromer budding . Results with TPA contrast a recent finding using p38 inhibitors in which a direct relationship was demonstrated between site 1 phosphorylation of OSBP and activation of SM synthesis at the Golgi apparatus …”

Section: Discussionmentioning

confidence: 61%

Protein kinase D1 and oxysterol‐binding protein form a regulatory complex independent of phosphorylation

Goto

Charman

Ridgway

2018

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Protein kinase D (PKD) controls secretion from the trans-Golgi network (TGN) by phosphorylating phosphatidylinositol 4-kinase IIIβ and proteins that bind and/or transfer phosphatidylinositol 4-phosphate (PtdIns-4P), such as oxysterol-binding protein (OSBP) and ceramide transfer protein. Here, we investigated the consequences of PKD phosphorylation of OSBP at endoplasmic reticulum (ER)-Golgi membrane contact sites (MCS). Results with OSBP phospho-mutants revealed that PKD phosphorylation did not affect sterol and PtdIns-4P binding, activation of sphingomyelin (SM) synthesis at Golgi-ER MCS or other OSBP phospho-sites. Instead, an interaction was identified between the N-terminal region of OSBP and PKD1 that was independent of kinase activity and OSBP phosphorylation status. S916 autophosphorylation of PKD1 was inhibited by OSBP expression suggesting the interaction negatively regulates PKD1 activity. Stimulation of PKD1 activity by phorbol ester promoted the Golgi-localization of wild-type and phospho-mutants of OSBP but did not affect OSBP-dependent SM synthesis. Only when wild-type or kinase-dead PKD1 was overexpressed was 25-hydroxycholesterol-activated SM synthesis inhibited. We conclude that OSBP and PKD1 form a complex that inhibits both the oxysterol-dependent activity of OSBP at the ER-Golgi and activation of PKD1. Formation of the complex was independent of PKD1 activity and phosphorylation of OSBP.

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“…In these cases, PI4P is transferred from the target membrane to the ER, where it is dephosphorylated by the resident protein Sac1 (Nemoto et al, 2000; Zewe et al, 2018). In the case of OSBP, PI4P is exchanged for cholesterol, which is transferred to the TGN or endosomes from the ER (Mesmin et al, 2013; Sobajima et al, 2018). ORP5 and ORP8 have been shown to transfer phosphatidylserine to the PM in exchange for PI4P(Chung et al, 2015), while ORP10 transfers PS from the ER to the TGN (Venditti et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex

D’Souza

Lim

Turgut

et al. 2019

Preprint

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17Coordinated assembly and disassembly of integrin-mediated focal adhesions (FAs) is essential for cell migration. 18 Many studies have shown that FA disassembly requires Ca 2+ influx, however our understanding of this process 19 remains incomplete. Here we show that Ca 2+ influx via STIM1/Orai1 calcium channels, which cluster near FAs, 20 leads to activation of the GTPase Arf5 via the Ca 2+ -activated GEF IQSec1, and that both IQSec1 and Arf5 21 activation are essential for adhesion disassembly. We further show that IQSec1 forms a complex with the lipid 22 transfer protein ORP3, and that Ca 2+ influx triggers PKC-dependent translocation of this complex to ER/plasma 23 membrane contact sites adjacent to FAs. In addition to allosterically activating IQSec1, ORP3 also extracts PI4P 24 from the PM, in exchange for phosphatidylcholine. ORP3-mediated lipid exchange is also important for FA 25 turnover. Together, these findings identify a new pathway that links calcium influx to FA turnover during cell 26 migration. 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 100 activation of Arf5 and insertion of PC into the plasma membrane are both important to promote adhesion 101disassembly. Taken together, our findings establish a spatial and mechanistic link between calcium influx at 102 ER/PM contact sites and focal adhesion turnover mediated by ORP3 and IQSec1-activated Arf5.

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The Rab11-binding protein RELCH/KIAA1468 controls intracellular cholesterol distribution

Abstract: Sobajima et al. identify the novel protein RELCH/KIAA1468 as a Rab11-binding protein and show that RELCH/KIAA1468 and Rab11 regulate OSBP-dependent nonvesicular cholesterol transport from recycling endosomes to the trans-Golgi network.

Cited by 47 publications

References 52 publications

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

In vivo identification of GTPase interactors by mitochondrial relocalization and proximity biotinylation

Protein kinase D1 and oxysterol‐binding protein form a regulatory complex independent of phosphorylation

Calcium-stimulated disassembly of focal adhesions mediated by an ORP3/IQSec1 complex

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