scholarly journals Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNFα

2007 ◽  
Vol 178 (1) ◽  
pp. 57-69 ◽  
Author(s):  
Anthony P. Manderson ◽  
Jason G. Kay ◽  
Luke A. Hammond ◽  
Darren L. Brown ◽  
Jennifer L. Stow
Keyword(s):  
Snare Proteins ◽  
Recycling Endosome ◽  
Recycling Endosomes ◽  
Trafficking Pathway ◽  
Protein Receptor ◽  
Cargo Proteins ◽  
Membrane Bound ◽  
Phagocytic Cups ◽  
Factor Α ◽  
Necrosis Factor

Activated macrophages secrete an array of proinflammatory cytokines, including tumor necrosis factor-α (TNFα) and interleukin 6 (IL-6), that are temporally secreted for sequential roles in inflammation. We have previously characterized aspects of the intracellular trafficking of membrane-bound TNFα and its delivery to the cell surface at the site of phagocytic cups for secretion (Murray, R.Z., J.G. Kay, D.G. Sangermani, and J.L. Stow. 2005. Science. 310:1492–1495). The trafficking pathway and surface delivery of IL-6, a soluble cytokine, were studied here using approaches such as live cell imaging of fluorescently tagged IL-6 and immunoelectron microscopy. Newly synthesized IL-6 accumulates in the Golgi complex and exits in tubulovesicular carriers either as the sole labeled cargo or together with TNFα, utilizing specific soluble NSF attachment protein receptor (SNARE) proteins to fuse with the recycling endosome. Within recycling endosomes, we demonstrate the compartmentalization of cargo proteins, wherein IL-6 is dynamically segregated from TNFα and from surface recycling transferrin. Thereafter, these cytokines are independently secreted, with TNFα delivered to phagocytic cups but not IL-6. Therefore, the recycling endosome has a central role in orchestrating the differential secretion of cytokines during inflammation.

Inhibition of phagocytosis in HIV-1–infected macrophages relies on Nef-dependent alteration of focal delivery of recycling compartments

Blood ◽  
2010 ◽  
Vol 115 (21) ◽  
pp. 4226-4236 ◽  
Author(s):  
Julie Mazzolini ◽  
Floriane Herit ◽  
Jérôme Bouchet ◽  
Alexandre Benmerah ◽  
Serge Benichou ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Adaptor Protein ◽  
Recycling Endosomes ◽  
Late Endosomes ◽  
Large Particles ◽  
Infected Cells ◽  
Phagocytic Cups ◽  
Factor Α ◽  
Hiv 1 ◽  
Necrosis Factor

Phagocytosis in macrophages is receptor mediated and relies on actin polymerization coordinated with the focal delivery of intracellular membranes that is necessary for optimal phagocytosis of large particles. Here we show that phagocytosis by various receptors was inhibited in primary human macrophages infected with wild-type HIV-1 but not with a nef-deleted virus. We observed no major perturbation of F-actin accumulation, but adaptor protein 1 (AP1)–positive endosome recruitment was inhibited in HIV-1–infected cells. Expression of negative factor (Nef) was sufficient to inhibit phagocytosis, and myristoylation as well as the LL and DD motifs involved in association of Nef with AP complexes were important for this inhibition. We observed that Nef interferes with AP1 in association with membranes and/or with a cleaved regulatory form of AP1. Finally, an alteration of the recruitment of vesicle-associated membrane protein (VAMP3)– and tumor necrosis factor-α (TNFα)–positive recycling endosomes regulated by AP1, but not of VAMP7-positive late endosomes, was observed in phagocytic cups of HIV-1–infected macrophages. We conclude that HIV-1 impairs optimal phagosome formation through Nef-dependent perturbation of the endosomal remodeling relying on AP1. We therefore identified a mechanism of macrophage function down-regulation in infected cells.

scholarly journals A TOCA/CDC-42/PAR/WAVE functional module required for retrograde endocytic recycling

2015 ◽  
Vol 112 (12) ◽  
pp. E1443-E1452 ◽  
Author(s):  
Zhiyong Bai ◽  
Barth D. Grant
Keyword(s):  
Functional Module ◽  
Small Gtpase ◽  
Recycling Endosome ◽  
Vesicle Budding ◽  
Recycling Endosomes ◽  
Physiological Importance ◽  
Golgi Transport ◽  
Early Endosomes ◽  
Cargo Proteins ◽  
Signaling Receptors

Endosome-to-Golgi transport is required for the function of many key membrane proteins and lipids, including signaling receptors, small-molecule transporters, and adhesion proteins. The retromer complex is well-known for its role in cargo sorting and vesicle budding from early endosomes, in most cases leading to cargo fusion with the trans-Golgi network (TGN). Transport from recycling endosomes to the TGN has also been reported, but much less is understood about the molecules that mediate this transport step. Here we provide evidence that the F-BAR domain proteins TOCA-1 and TOCA-2 (Transducer of Cdc42 dependent actin assembly), the small GTPase CDC-42 (Cell division control protein 42), associated polarity proteins PAR-6 (Partitioning defective 6) and PKC-3/atypical protein kinase C, and the WAVE actin nucleation complex mediate the transport of MIG-14/Wls and TGN-38/TGN38 cargo proteins from the recycling endosome to the TGN in Caenorhabditis elegans. Our results indicate that CDC-42, the TOCA proteins, and the WAVE component WVE-1 are enriched on RME-1–positive recycling endosomes in the intestine, unlike retromer components that act on early endosomes. Furthermore, we find that retrograde cargo TGN-38 is trapped in early endosomes after depletion of SNX-3 (a retromer component) but is mainly trapped in recycling endosomes after depletion of CDC-42, indicating that the CDC-42–associated complex functions after retromer in a distinct organelle. Thus, we identify a group of interacting proteins that mediate retrograde recycling, and link these proteins to a poorly understood trafficking step, recycling endosome-to-Golgi transport. We also provide evidence for the physiological importance of this pathway in WNT signaling.

scholarly journals Endocytosis and Recycling of the HIV Coreceptor Ccr5

2000 ◽  
Vol 151 (6) ◽  
pp. 1281-1294 ◽  
Author(s):  
Nathalie Signoret ◽  
Annegret Pelchen-Matthews ◽  
Matthias Mack ◽  
Amanda E.I. Proudfoot ◽  
Mark Marsh
Keyword(s):  
Cell Surface ◽  
Chemokine Receptor ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Recycling Endosome ◽  
Recycling Endosomes ◽  
Chemokine Receptor Ccr5 ◽  
Human Immunodeficiency Viruses ◽  
Membrane Bound ◽  
Induced Changes

The chemokine receptor CCR5 is a cofactor for the entry of R5 tropic strains of human immunodeficiency viruses (HIV)-1 and -2 and simian immunodeficiency virus. Cells susceptible to infection by these viruses can be protected by treatment with the CCR5 ligands regulated on activation, normal T cell expressed and secreted (RANTES), MIP-1α, and MIP-1β. A major component of the mechanism through which chemokines protect cells from HIV infection is by inducing endocytosis of the chemokine receptor. Aminooxypentane (AOP)-RANTES, an NH2-terminal modified form of RANTES, is a potent inhibitor of infection by R5 HIV strains. AOP-RANTES efficiently downmodulates the cell surface expression of CCR5 and, in contrast with RANTES, appears to prevent recycling of CCR5 to the cell surface. Here, we investigate the cellular basis of this effect. Using CHO cells expressing human CCR5, we show that both RANTES and AOP-RANTES induce rapid internalization of CCR5. In the absence of ligand, CCR5 shows constitutive turnover with a half-time of 6–9 h. Addition of RANTES or AOP-RANTES has little effect on the rate of CCR5 turnover. Immunofluorescence and immunoelectron microscopy show that most of the CCR5 internalized after RANTES or AOP-RANTES treatment accumulates in small membrane-bound vesicles and tubules clustered in the perinuclear region of the cell. Colocalization with transferrin receptors in the same clusters of vesicles indicates that CCR5 accumulates in recycling endosomes. After the removal of RANTES, internalized CCR5 recycles to the cell surface and is sensitive to further rounds of RANTES-induced endocytosis. In contrast, after the removal of AOP-RANTES, most CCR5 remains intracellular. We show that these CCR5 molecules do recycle to the cell surface, with kinetics equivalent to those of receptors in RANTES-treated cells. However, these recycled CCR5 molecules are rapidly reinternalized. Our results indicate that AOP-RANTES–induced changes in CCR5 alter the steady-state distribution of the receptor and provide the first evidence for G protein–coupled receptor trafficking through the recycling endosome compartment.

scholarly journals Dysregulation of Membrane-Bound Tumor Necrosis Factor-α and Tumor Necrosis Factor Receptors on Mononuclear Cells in Human Immunodeficiency Virus Type 1 Infection: Low Percentage of p75-Tumor Necrosis Factor Receptor Positive Cells in Patients With Advanced Disease and High Viral Load

Blood ◽  
1997 ◽  
Vol 90 (7) ◽  
pp. 2670-2679
Author(s):  
Kjetil Hestdal ◽  
Pål Aukrust ◽  
Fredrik Müller ◽  
Egil Lien ◽  
Vigdis Bjerkeli ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Mononuclear Cells ◽  
Healthy Controls ◽  
Aids Patients ◽  
Tnf Α ◽  
Membrane Bound ◽  
Factor Α ◽  
Hiv 1 ◽  
Necrosis Factor

The correlation of persistent tumor necrosis factor-α (TNF-α) activation with disease progression in patients infected with human immunodeficiency virus type 1 (HIV-1), suggests a role for TNF-α in the pathogenesis of HIV-1 infection. In the present study, we examined by flow cytometry the expression of membrane-bound (m) components of the TNF system in 33 HIV-1–infected patients and 12 healthy controls. While peripheral blood mononuclear cells (PBMC) from asymptomatic and symptomatic non-acquired immune deficiency syndrome (AIDS) patients showed a significantly increased percentage of mTNF-α+ and mTNF receptor (TNFR)+ cells compared with controls, this was not found in the AIDS group. Compared with healthy controls, AIDS patients had a significantly decreased percentage of both monocytes and lymphocytes expressing p75-TNFR. PBMC from AIDS patients showed a higher p75-TNFR mRNA level and a higher spontaneous release of soluble p75-TNFR than healthy individuals, suggesting enhanced cell surface turnover of this TNFR. The low expression of TNFRs on both lymphocytes and monocytes in the AIDS group was associated with high numbers of HIV-1 RNA copies in plasma, low numbers of CD4+ lymphocytes, and high serum levels of soluble TNFRs. AIDS patients had a decreased percentage of CD8+ lymphocytes expressing TNFRs compared with healthy controls. In contrast, these patients, as well as symptomatic non-AIDS patients, had an increased percentage of TNF-α+ and TNFRs+ cells among remaining CD4+ lymphocytes. The pattern of abnormalities seen in AIDS patients suggests a role for persistent activation of the TNF system in the accelerated CD4+ lymphocyte destruction, the enhanced HIV-1 replication, and the markedly impaired antimicrobial defense in advanced HIV-1-related disease.

scholarly journals The Rab11-Family Interacting Proteins reveal selective interaction of mammalian recycling endosomes with the Toxoplasma parasitophorous vacuole in a Rab11- and Arf6-dependent manner

2021 ◽  
Author(s):  
Eric J Hartman ◽  
Julia D Romano ◽  
Isabelle Coppens
Keyword(s):  
Mammalian Cells ◽  
Parasitophorous Vacuole ◽  
Class Ii ◽  
Class I ◽  
Dependent Manner ◽  
Interacting Proteins ◽  
Cell Organelles ◽  
Recycling Endosome ◽  
Recycling Endosomes ◽  
Membrane Bound

After invasion of mammalian cells, the parasite Toxoplasma gondii multiplies in a self-made membrane-bound compartment, the parasitophorous vacuole (PV). We previously showed that intravacuolar Toxoplasma interacts with many host cell organelles, especially recycling endosomes, and further manipulates the host endocytic recycling through the sequestration of Rab11 vesicles into the PV. Mammalian Rab-PV interactions are likely mediated by Toxoplasma and host proteins that remain to be identified. In this context, we have examined the specificity of host Rab vesicle interaction with the PV by monitoring the recruitment of subtypes of Rab11 vesicles differing in their composition in Rab11-Family Interacting Proteins (FIPs). We found that vesicles with FIPs from Class I (FIP1C, FIP2, FIP5) or Class II (FIP3, FIP4) are distributed at the PV and detected to varying degrees inside the PV. The PV delivery of vesicles with FIPs from Class I, but not Class II, is Rab11-dependent. In addition to Rab11, FIP3 binds to Arf6, and vesicles associated with FIP3-Arf6 complexes are observed within the PV. Binding of FIP3 to either Rab11 or Arf6 significantly increases the internalization of vesicles into the PV. These data point to a selective process of host recycling endosome recognition and scavenging mediated by Toxoplasma.

Suppressor activity among CD4+,CD25++ T cells is discriminated by membrane-bound tumor necrosis factor α

2008 ◽  
Vol 58 (6) ◽  
pp. 1609-1618 ◽  
Author(s):  
Jun Wang ◽  
Henrike van Dongen ◽  
Hans Ulrich Scherer ◽  
Tom W. J. Huizinga ◽  
Rene E. M. Toes
Keyword(s):  
T Cells ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Suppressor Activity ◽  
Membrane Bound ◽  
Factor Α ◽  
Necrosis Factor

scholarly journals A Second SNARE Role for Exocytic SNAP25 in Endosome Fusion

2006 ◽  
Vol 17 (5) ◽  
pp. 2113-2124 ◽  
Author(s):  
Yoshikatsu Aikawa ◽  
Kara L. Lynch ◽  
Kristin L. Boswell ◽  
Thomas F.J. Martin
Keyword(s):  
Plasma Membrane ◽  
Membrane Fusion ◽  
Secretory Vesicle ◽  
Neuroendocrine Cells ◽  
Snare Complex ◽  
Snare Proteins ◽  
Recycling Endosome ◽  
Protein Receptor ◽  
Interfering Rna

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins play key roles in membrane fusion, but their sorting to specific membranes is poorly understood. Moreover, individual SNARE proteins can function in multiple membrane fusion events dependent upon their trafficking itinerary. Synaptosome-associated protein of 25 kDa (SNAP25) is a plasma membrane Q (containing glutamate)-SNARE essential for Ca2+-dependent secretory vesicle–plasma membrane fusion in neuroendocrine cells. However, a substantial intracellular pool of SNAP25 is maintained by endocytosis. To assess the role of endosomal SNAP25, we expressed botulinum neurotoxin E (BoNT E) light chain in PC12 cells, which specifically cleaves SNAP25. BoNT E expression altered the intracellular distribution of SNAP25, shifting it from a perinuclear recycling endosome to sorting endosomes, which indicates that SNAP25 is required for its own endocytic trafficking. The trafficking of syntaxin 13 and endocytosed cargo was similarly disrupted by BoNT E expression as was an endosomal SNARE complex comprised of SNAP25/syntaxin 13/vesicle-associated membrane protein 2. The small-interfering RNA-mediated down-regulation of SNAP25 exerted effects similar to those of BoNT E expression. Our results indicate that SNAP25 has a second function as an endosomal Q-SNARE in trafficking from the sorting endosome to the recycling endosome and that BoNT E has effects linked to disruption of the endosome recycling pathway.

LIR9, an immunoglobulin-superfamily–activating receptor, is expressed as a transmembrane and as a secreted molecule

Blood ◽  
2003 ◽  
Vol 101 (4) ◽  
pp. 1484-1486 ◽  
Author(s):  
Luis Borges ◽  
Marek Kubin ◽  
Tracy Kuhlman
Keyword(s):  
Immune Responses ◽  
Innate Immune ◽  
Calcium Flux ◽  
Immunoglobulin Superfamily ◽  
Innate Immune Responses ◽  
Transmembrane Region ◽  
Tnf Α ◽  
Membrane Bound ◽  
Factor Α ◽  
Necrosis Factor

LIRs are immunoglobulinlike receptors that have activating and inhibitory functions in leukocytes. Here we report the identification of the first LIR family member, LIR9, expressed as a membrane-bound receptor and as a secreted molecule. We identified 4 different forms of LIR9, 2 of which encode transmembrane molecules and 2 encode secreted molecules. The transmembrane forms of LIR9 contain a short cytoplasmic domain and a charged arginine residue within the transmembrane region that is likely to mediate its association with another coreceptor. LIR9 is mostly expressed in myeloid cells, including monocytes and neutrophils. Cross-linking of LIR9 on the surfaces of monocytes induces calcium flux and secretion of the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, indicating that LIR9 could play a role in triggering innate immune responses.

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