Inhibition of T-Cell Receptor-Induced Actin Remodeling and Relocalization of Lck Are Evolutionarily Conserved Activities of Lentiviral Nef Proteins

Rudolph, Jochen M.; Eickel, Nina; Haller, Claudia; Schindler, Michael; Fackler, Oliver T.

doi:10.1128/jvi.01423-09

Cited by 41 publications

(73 citation statements)

References 42 publications

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“…At this time point, control cells displayed hallmarks of early T cell activation, including cell spreading and formation of circumferential F-actin rings, both of which were potently inhibited by the presence of Nef, as reported earlier (Fig. 1A) (37)(38)(39)48). Coexpression of the TCR z-chain fused to GFP (TCR.GFP) in these cells revealed the formation of numerous MCs at cell-cover glass stimulatory contacts that were distributed across the entire cell diameter, including its periphery (see schematic in Supplemental Fig.…”

Section: Early Tcr MC Formation Is Undisturbed In the Presence Of Nefsupporting

confidence: 83%

“…1). As described previously (37,39,40,49), Nef localized to the plasma membrane, diffusely in the cytoplasm and at a perinuclear compartment, but was not detected in MCs. Quantification of the frequency of cells that displayed TCR MCs revealed that Nef did not significantly affect their overall occurrence (Fig.…”

Section: Early Tcr MC Formation Is Undisturbed In the Presence Of Nefsupporting

confidence: 77%

“…Early TCR signaling events are markedly decreased by the viral protein, reflecting its ability to reduce the frequency of stimulatory cell-cell contacts (39) and to limit LAT-SLP-76-mediated signaling. Possibly reflecting a high selective pressure on this Nef activity, disruption of TCRproximal events is mediated by two synergistic mechanisms affecting host cell actin dynamics and vesicular transport.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, HIV-1 Nef severely impairs the formation and organization of IS structures between Nef-expressing T lymphocytes and APCs by reducing the frequency of IS formation, blocking Factin polarization at cell-cell contacts, and inducing mislocalization of the TCR itself as well as its effector kinase Lck (28,(35)(36)(37)(38)(39). These morphological alterations at the IS were accompanied by interference with early TCR signaling such as induction of tyrosine phosphorylation (36,37,39). We recently reported that Nef achieves enhanced T cell activation responses despite this disruption of early signaling events by the assembly of active signaling complexes at the trans Golgi network (TGN) (40).…”

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confidence: 99%

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HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Abraham

Bankhead

Pan

et al. 2012

The Journal of Immunology

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Signal initiation by engagement of the TCR triggers actin rearrangements, receptor clustering, and dynamic organization of signaling complexes to elicit and sustain downstream signaling. Nef, a pathogenicity factor of HIV, disrupts early TCR signaling in target T cells. To define the mechanism underlying this Nef-mediated signal disruption, we employed quantitative single-cell microscopy following surface-mediated TCR stimulation that allows for dynamic visualization of distinct signaling complexes as microclusters (MCs). Despite marked inhibition of actin remodeling and cell spreading, the induction of MCs containing TCR-CD3 or ZAP70 was not affected significantly by Nef. However, Nef potently inhibited the subsequent formation of MCs positive for the signaling adaptor Src homology-2 domain-containing leukocyte protein of 76 kDa (SLP-76) to reduce MC density in Nef-expressing and HIV-1–infected T cells. Further analyses suggested that Nef prevents formation of SLP-76 MCs at the level of the upstream adaptor protein, linker of activated T cells (LAT), that couples ZAP70 to SLP-76. Nef did not disrupt pre-existing MCs positive for LAT. However, the presence of the viral protein prevented de novo recruitment of active LAT into MCs due to retargeting of LAT to an intracellular compartment. These modulations in MC formation and composition depended on Nef’s ability to simultaneously disrupt both actin remodeling and subcellular localization of TCR-proximal machinery. Nef thus employs a dual mechanism to disturb early TCR signaling by limiting the communication between LAT and SLP-76 and preventing the dynamic formation of SLP-76–signaling MCs.

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Section: Early Tcr MC Formation Is Undisturbed In the Presence Of Nefsupporting

confidence: 83%

Section: Early Tcr MC Formation Is Undisturbed In the Presence Of Nefsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

Abraham

Bankhead

Pan

et al. 2012

The Journal of Immunology

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“…How these functions individually contribute to the prominent role of Nef in AIDS pathogenesis remains to be established. Inhibition of dynamic host cell actin remodeling, mediated via association with the cellular kinase PAK2 that induces inactivation of the actin-severing factor cofilin to reduce actin turnover, represents a conserved activity of lentiviral Nef proteins (2)(3)(4)(5)(6)(7)(8). Nef-PAK2 association depends on a critical phenylalanine at position 195 of Nef (or 191 depending on the HIV-1 nef allele analyzed) that is dispensable for other Nef activities (9).…”

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confidence: 99%

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

Stolp

Imle

Coelho

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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HIV-1 negative factor (Nef) elevates virus replication and contributes to immune evasion in vivo. As one of its established in vitro activities, Nef interferes with T-lymphocyte chemotaxis by reducing host cell actin dynamics. To explore Nef’s influence on in vivo recirculation of T lymphocytes, we assessed lymph-node homing of Nef-expressing primary murine lymphocytes and found a drastic impairment in homing to peripheral lymph nodes. Intravital imaging and 3D immunofluorescence reconstruction of lymph nodes revealed that Nef potently impaired T-lymphocyte extravasation through high endothelial venules and reduced subsequent parenchymal motility. Ex vivo analyses of transendothelial migration revealed that Nef disrupted T-lymphocyte polarization and interfered with diapedesis and migration in the narrow subendothelial space. Consistently, Nef specifically affected T-lymphocyte motility modes used in dense environments that pose high physical barriers to migration. Mechanistically, inhibition of lymph node homing, subendothelial migration and cell polarization, but not diapedesis, depended on Nef’s ability to inhibit host cell actin remodeling. Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and thus represents an important mechanism for its function as a HIV pathogenicity factor.

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Nef does not inhibit F-actin remodelling and HIV-1 cell–cell transmission at the T lymphocyte virological synapse

Haller

Tibroni

Rudolph

et al. 2011

European Journal of Cell Biology

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Inhibition of T-Cell Receptor-Induced Actin Remodeling and Relocalization of Lck Are Evolutionarily Conserved Activities of Lentiviral Nef Proteins

Cited by 41 publications

References 42 publications

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

HIV-1 Nef Limits Communication between Linker of Activated T Cells and SLP-76 To Reduce Formation of SLP-76–Signaling Microclusters following TCR Stimulation

HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo

Nef does not inhibit F-actin remodelling and HIV-1 cell–cell transmission at the T lymphocyte virological synapse

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