The Formin Family Protein, Formin Homolog Overexpressed in Spleen, Interacts with the Insulin-Responsive Aminopeptidase and Profilin IIa

Tojo, Hideaki; Kaieda, Isao; Hattori, Harumi; Katayama, Nozomi; Yoshimura, Koji; Kakimoto, Shigeya; Fujisawa, Yukio; Presman, Eleonora; Brooks, Cydney C.; Pilch, Paul F.

doi:10.1210/me.2003-0056

Cited by 44 publications

(42 citation statements)

References 42 publications

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“…TLR9 are retained, we screen for cytoskeletal proteins that might interact with IRAP and could interfere with endosomal motility. Indeed, considering that the cytosolic tail of IRAP was shown to interact with two cytoskeleton components, an actin nucleation factor, the formin FHOD1 20 and the intermediate filament vimentin 19 , we hypothesized that these interactions ensure the anchoring of IRAP and TLR9 endosomes to cytoskeleton. Whereas the interaction of IRAP with vimentin was not detectable in DCs (experiments not shown), we found that IRAP binds to FHOD4 formin.…”

Section: ! Disscussionmentioning

confidence: 99%

“…The regulated trafficking of IRAP depends on the cytosolic domain of the enzyme, which has been shown to interact with several proteins involved in vesicle formation or in cytoskeleton remodeling, such as the golgin p115 18 , vimentin 19 and FHOS (formin homologue overexpressed in the spleen, also called FHOD1) 20 . Whether these proteins and their interaction with the cytosolic domain of IRAP play a role in the trafficking of IRAP + endosomes is not known.…”

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IRAP+ endosomes restrict TLR9 activation and signaling

et al. 2017

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Retention of intracellular Toll-Like Receptors (TLRs) in the endoplasmic reticulum prevents their activation under basal conditions. TLR9 is activated by sensing ligands in specific endosomal/lysosomal compartments. Here, we describe the identification of insulin responsive aminopeptidase (IRAP) endosomes as major cellular compartments for the early steps of TLR9 activation in dendritic cells (DCs). Both TLR9 and its ligand CpG were found as cargo in IRAP endosomes. In the absence of IRAP, CpG and TLR9 trafficking to lysosomes and TLR9 signaling were enhanced in DCs and in mice following bacterial infection. IRAP stabilized CpG-containing endosomes by interacting with the actin nucleation factor FHOD4, slowing down TLR9 trafficking towards lysosomes. Thus, endosome retention of TLR9 via IRAP interaction with the actin cytoskeleton is a mechanism that prevents TLR9hyper-activation in DCs. discriminate between different classes of microbial products and initiate specific signaling cascades. While microbial products with no equivalent in mammalian cells, such as the components of the bacterial wall, are recognized by surface TLRs (1, 2, 4, 5 and 6), pathogen derived nucleic acids are sensed by intracellular TLRs (3,7, 8 and 9). Recognition of nucleic acids by intracellular TLRs has the potential to trigger autoimmune diseases through interaction with self nucleic acids 1 . To avoid inappropriate activation of endosomal TLRs, their trafficking is tightly controlled. Thus, in basal conditions the receptors are located in the endoplasmic reticulum (ER) and translocate to endocytic vesicles only after cell stimulation by TLR ligands. Although all intracellular TLRs reside in the ER 2,3 , the trafficking pathways that move the receptors into the endocytic pathway show considerable variation among intracellular TLRs 4-6 . For example, TLR7 traffics from Golgi stacks directly to endosomes using the clathrin adaptor AP4, whereas the TLR9 is directed to the cell surface and reaches the endosomes via AP2-mediated clathrin-dependent endocytosis 6 .In addition to the transfer into the endocytic pathway, a second step that controls the activation of endosomal TLRs is their partial proteolysis by an array of different proteases, specific for each TLR 5,7-12 .Although less often mentioned, the intracellular trafficking of its ligand also controls the activation of TLR9. TLR9 ligands (CpG) are internalized via clathrin-mediated endocytosis in early endosomes and translocate to late LAMP + compartments 2 . TLR9 activation depends on CpG localization, since the abrogation of CpG translocation to LAMP + compartments by specific inhibitors decreased TLR9 signaling 13,14 . Thus, the intracellular trafficking of both, the ligand and the receptor are essential for the control of TLR9 activation. RESULTS IRAP deletion increases TLR9 responseTo address the role of IRAP in TLRs signaling, wild-type and IRAP-deficient bone marrow derived dendritic cells (BMDCs) were stimulated with specific TLR ligands: polyIC for TLR3, Imiquimod fo...

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IRAP+ endosomes restrict TLR9 activation and signaling

et al. 2017

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“…IRAP being a membrane protein that contains two dileucine motifs with a preceding acidic cluster ( 40 EPDEVEYEPRGSRLL 54 , 64 DEDEEDYESSAKLL 77 ), injection of the IRAP55-82 induced GLUT4 translocation in 3T3-L1 adipocytes, suggesting that IRAP interacts with a sorting and targeting protein regulating GLUT4 translocation (10)(11)(12). IRAP55-82 has also been shown to associate with acyl-coenzyme A dehydrogenase (13) and formin homolog over-expressed in spleen (14). Furthermore, IRAP1-109 has been shown to interact with p115 (15), and a defined sequence ( 96 RQSPDG 101 ) has been shown to be involved in binding to the ankyrin repeats of tankyrase (16).…”

Section: Irap Of Residue 1-49 Is the Major Site Of Tbc1d4 Ptb2 Interamentioning

confidence: 99%

Affinity between TBC1D4 (AS160) phosphotyrosine-binding domain and insulin-regulated aminopeptidase cytoplasmic domain measured by isothermal titration calorimetry

Park¹,

Kim²,

Kim³

et al. 2012

BMB Reports

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Uptake of circulating glucose into the cells happens via the insulin-mediated signalling pathway, which translocates the glucose transporter 4 (GLUT4) vesicles from the intracellular compartment to the plasma membrane. RabㆍGTPases are involved in this vesicle trafficking, where RabㆍGTPase-activating proteins (RabGAP) enhance the GTP to GDP hydrolysis. TBC1D4 (AS160) and TBC1D1 are functional RabGAPs in the adipocytes and the skeletonal myocytes, respectively. These proteins contain two phosphotyrosine-binding domains (PTBs) at the amino-terminus of the catalytic RabGAP domain. The second PTB has been shown to interact with the cytoplasmic region of the insulin-regulated aminopeptidase (IRAP) of the GLUT4 vesicle. In this study, we quantitatively measured the ∼μM affinity (KD) between TBC1D4 PTB and IRAP using isothermal titration calorimetry, and further showed that IRAP residues 1-49 are the major region mediating this interaction. We also demonstrated that the IRAP residues 1-15 are necessary but not sufficient for the PTB interaction. [BMB Reports 2012; 45(6): 360-364]

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“…Formins are critical for cytokinesis, for the establishment of cell polarity and for control of morphogenesis. FHOS, a human formin first identified in a spleen library has been shown to interact with the small GTPase Rac1, to bind the actin binding protein profilin IIa and to activate the serum response transcription factor in vitro (Tojo et al, 2003;Westendorf, 2001). Recent studies indicate that FHOS can interact with actin monomers and may play a role in the regulation of cell motility and vesicle recycling as well (Koka et al, 2003;Tojo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

EBV attachment stimulates FHOS/FHOD1 redistribution and co-aggregation with CD21: formin interactions with the cytoplasmic domain of human CD21

Gill

Roecklein‐Canfield

Sage

et al. 2004

Journal of Cell Science

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CD21 is a multifunctional receptor for Epstein-Barr virus (EBV), for C3dg and for CD23. Upon engagement of immune complexes CD21 modulates immunoreceptor signaling, linking innate and adaptive immune responses. The mechanisms enabling CD21 to independently relay information between the exterior and interior of the cell, however, remain unresolved. We show that formin homologue overexpressed in spleen (FHOS/FHOD1) binds the cytoplasmic domain of human CD21 through its C terminus. When expressed in cells, EGFP-FHOS localizes to the cytoplasm and accumulates with actin in membrane protrusions. Plasma membrane aggregation, redistribution and co-localization of both proteins are stimulated when EBV (ligand) binds CD21. Though widely expressed, FHOS RNA is most abundant in the littoral cell, a major constituent of the red pulp of human spleen believed to function in antigen filtration. Formins are molecular scaffolds that nucleate actin by a pathway distinct from Arp2/3 complex, linking signal transduction to actin reorganization and gene transcription. Thus, ligand stimulation of FHOS-CD21 interaction may transmit signals through promotion of cytoskeletal rearrangement. Moreover, formin recruitment to sites of actin assembly initiated by immunoreceptors could be a general mechanism whereby co-receptors such as CD21 modulate intracellular signaling.

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The Formin Family Protein, Formin Homolog Overexpressed in Spleen, Interacts with the Insulin-Responsive Aminopeptidase and Profilin IIa

Cited by 44 publications

References 42 publications

IRAP+ endosomes restrict TLR9 activation and signaling

IRAP+ endosomes restrict TLR9 activation and signaling

Affinity between TBC1D4 (AS160) phosphotyrosine-binding domain and insulin-regulated aminopeptidase cytoplasmic domain measured by isothermal titration calorimetry

EBV attachment stimulates FHOS/FHOD1 redistribution and co-aggregation with CD21: formin interactions with the cytoplasmic domain of human CD21

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