Vimentin binds IRAP and is involved in GLUT4 vesicle trafficking

Hirata, Y; Hosaka, Toshio; Iwata, Takeo; Le, Chung T.K.; Jambaldorj, Bayasgalan; Takamatsu, Kiyoshi; Harada, Nagakatsu; Sakaue, Hiroshi; Sakai, Tohru; Yoshimoto, Katsuhiko; Nakaya, Yutaka

doi:10.1016/j.bbrc.2010.12.134

Cited by 20 publications

(18 citation statements)

References 43 publications

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“…In particular, AR was positively associated with the expression of SYNT5, SNAP23, and VAMP4, which encode for proteins belonging to the SNARE complex, crucially involved in the processes of lipid droplet formation (Boström et al 2007). Besides the positive association with GLUT4, AR mRNA also correlated with RHOA, ROCK2, and VIM, all proteins implicated in the cytoskeleton remodeling required for the insulinstimulated intracellular trafficking of GLUT4 vesicles (Hirata et al 2011, Chun et al 2012. Moreover, a highly significant positive correlation was found between AR and STAMP2, whose expression is required for normal insulin signaling, as demonstrated in loss-of-function studies (Wellen et al 2007).…”

Section: Discussionmentioning

confidence: 97%

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Maneschi¹,

Morelli²,

Filippi³

et al. 2012

Journal of Endocrinology

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We recently demonstrated that testosterone dosing ameliorated the metabolic profile and reduced visceral adipose tissue (VAT) in a high-fat diet (HFD)-induced rabbit model of metabolic syndrome (MetS). We studied the effects of HFD and in vivo testosterone dosing on VAT function and the adipogenic capacity of rabbit preadipocytes isolated from VAT of regular diet (RD), HFD, and testosterone-treated HFD rabbits. VAT was studied by immunohistochemistry, western blot, and RT-PCR. Isolated rPADs were exposed to adipocyte differentiating mixture (DIM) to evaluate adipogenic potential. Adipocyte size was significantly increased in HFD VAT compared with RD, indicating adipocyte dysfunction, which was normalized by testosterone dosing. Accordingly, perilipin, an anti-lipolytic protein, was significantly increased in HFD VAT, when compared with other groups. HFD VAT was hypoxic, while testosterone dosing normalized VAT oxygenation. In VAT, androgen receptor expression was positively associated with mRNA expression of GLUT4 (SLC2A4) (insulin-regulated glucose transporter) and STAMP2 (STEAP4) (androgen-dependent gene required for insulin signaling). In testosterone-treated HFD VAT, STAMP2 mRNA was significantly increased when compared with the other groups. Moreover, GLUT4 membrane translocation was significantly reduced in HFD VAT, compared with RD, and increased by testosterone. In DIM-exposed preadipocytes from HFD, triglyceride accumulation, adipocyte-specific genes, insulin-stimulated triglyceride synthesis, glucose uptake, and GLUT4 membrane translocation were reduced compared with preadipocytes from RD and normalized by in vivo testosterone dosing. In conclusion, testosterone dosing in a MetS animal model positively affects VAT functions. This could reflect the ability of testosterone in restoring insulin sensitivity in VAT, thus counteracting metabolic alterations.

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Section: Discussionmentioning

confidence: 97%

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Maneschi¹,

Morelli²,

Filippi³

et al. 2012

Journal of Endocrinology

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“…Given that the N-terminal cytosolic tail of IRAP interacts with several proteins implicated in protein sorting, vesicle formation and cytoskeleton remodeling, we speculate that recruitment of IRAP-containing vesicles may function as a shuttle, delivering important yet undefined proteins at the cell surface to respond against LPS or exogenous particles. 3,20,[57][58][59][60] The C-type lectin receptor MMR is responsible for receptor-mediated endocytosis of antigens containing highmannose structures (such as OVA). 61 MMR has been shown to be associated with AP-N in the macrophage cell line J774, 8 and in dendritic cells, MMR colocalizes up to 75% with IRAP.…”

Section: Discussionmentioning

confidence: 99%

Presence and regulation of insulin-regulated aminopeptidase in mouse macrophages

Nikolaou

Stijlemans

Laoui

et al. 2014

J Renin Angiotensin Aldosterone Syst

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Introduction: The insulin-regulated aminopeptidase (IRAP) is expressed in several cell types, where it is mainly located in specialized secretory endosomes that are quickly recruited to the cell surface upon cell type-specific activation. Here we describe for the first time the expression and subcellular distribution of IRAP in macrophages. Methods: IRAP mRNA expression, protein expression and presence at the cell surface was investigated by real-time polymerase chain reaction (PCR), Western blot and [³H]IVDE77 binding, respectively. Results: IRAP mRNA expression was increased by interferon-γ (IFN-γ) and lipopolysaccharide (LPS), but not by antiinflammatory cytokines (interleukin (IL)-4, IL-10, transforming growth factor β (TGF-β)). IFN-γ increased [³H]IVDE77 binding steadily over time, while LPS quickly and transiently recruited IRAP to the cell surface. Combined stimulations with IFN-γ and LPS showed the same pattern as LPS alone. Latex particles also induced a transient recruitment of IRAP to the cell surface, but no difference was observed in phagocytic uptake between wild-type and IRAP -/-macrophages, suggesting that the enzymatic activity of IRAP is not required for the ingestion of particles. Conclusion: IRAP is more highly expressed in pro-inflammatory M1-activated macrophages and its presence at the cell surface is modulated upon exposure to IFN-γ, LPS or exogenous particles.

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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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confidence: 99%

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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Vimentin binds IRAP and is involved in GLUT4 vesicle trafficking

Cited by 20 publications

References 43 publications

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Testosterone treatment improves metabolic syndrome-induced adipose tissue derangements

Presence and regulation of insulin-regulated aminopeptidase in mouse macrophages

IRAP+ endosomes restrict TLR9 activation and signaling

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