HIV Nef, Paxillin, and Pak1/2 Regulate Activation and Secretion of TACE/ADAM10 Proteases

Lee, Jung-Hyun; Wittki, Sebastian; Bräu, Tanja; Dreyer, Florian S.; Krätzel, K.; Dindorf, Jochen; Johnston, Ian; Groß, Stefanie; Kremmer, Elisabeth; Zeidler, Reinhard; Schlötzer‐Schrehardt, Ursula; Lichtenheld, Mathias G.; Saksela, Kalle; Harrer, Thomas; Schuler, Gerold; Federico, Maurizio; Baur, Andreas S.

doi:10.1016/j.molcel.2012.12.004

Cited by 87 publications

(120 citation statements)

References 51 publications

Supporting

Mentioning

112

Contrasting

Order By: Relevance

“…Several potential cellular substrates for the Nef-PAK2 complex have been reported. These include Bad, 166 Merlin, 167 cofilin, 168 and, as recently reported, also paxillin 169 and Mek1. 170 Nef has been implicated in changes in the actin cytoskeleton late in HIV-infection, consisting of the formation of long cellular extensions, which depend on the GEF activity of Vav.…”

supporting

confidence: 69%

“…As a consequence, peripheral blood mononuclear cells (PBMCs) that ingested these EV released TNFα, which may promote viral replication by creating a favorable microenvironment. 169 Furthermore, HIV-mediated interference with Rho GTPase signaling in endothelial cells may affect brain homeostasis by disrupting the blood-brain barrier (BBB). The BBB prevents the entrance of circulating molecules and immune cells into the central nervous system by forming specialized brain endothelial cells that are connected by tight junctions (TJ).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Rho’ing in and out of cells

2014

View full text Add to dashboard Cite

These authors contributed equally to this work Keywords: Rho GTPase, actin, egress, entry, gene expression, immune system, transformation, virus Rho GTPases are key regulators of actin and microtubule dynamics and organization. increasing evidence shows that many viruses have evolved diverse interactions with Rho GTPase signaling and manipulate them for their own benefit. in this review, we discuss how Rho GTPase signaling interferes with many steps in the viral replication cycle, especially entry, replication, and spread. Seen the diversity between viruses, it is not surprising that there is considerable variability in viral interactions with Rho GTPase signaling. However, several largely common effects on Rho GTPases and actin architecture and microtubule dynamics have been reported. For some of these processes, the molecular signaling and biological consequences are well documented while for others we just begin to understand them. A better knowledge and identification of common threads in the different viral interactions with Rho GTPase signaling and their ultimate consequences for virus and host may pave the way toward the development of new antiviral drugs that may target different viruses.©2014 Landes Bioscience. Do not distribute. e28318-2Small GTPases volume 5effector of ROCK, which phosphorylates and inhibits cofilin.14 Cofilin is an F-actin-severing protein. Mainly depending on the local availability of G-actin monomers, cofilin activity may lead to net actin depolymerization or increased actin polymerization and branching. Other RhoA effectors include members of the ezrin/radixin/moesin (ERM) proteins 15 . Rac1 is thought to release WAVE from an inhibited complex, thereby activating the actin-polymerizing complex Arp2/3. 16,17 Active Arp2/3 mediates branching and elongation of existing actin filaments, generating a meshwork. Cdc42 also activates Arp2/3 through a direct interaction with the Arp2/3 activators Wiskott-Aldrich syndrome protein (WASP) or N-WASP.18 Both Rac1 and Cdc42 also activate group I serine/threonine p21 activating kinases (PAK). These different signalization branches are interconnected. In general, RhoA pathway signaling counteracts the Rac1 and Cdc42 signaling axes and vice versa.Because Rho GTPase signaling is involved in a plethora of cellular processes, it is perhaps not surprising that several viral gene products have evolved to interfere with and modulate these signaling axes. Indeed, several viruses interfere with the actin cytoskeleton and Rho GTPase signaling during many steps of their replication cycle. During entry and egress, these interactions may allow or facilitate viral particle passage across the cortical actin barrier and to rearrange actin to conformations that promote virus infection and spread, while other viral processes, such as intracellular movement, gene expression and latency, but also interaction with the immune system or oncogenesis may also depend to some extent on Rho GTPase signaling and associated actin rearrangements. In this review, the current kno...

show abstract

supporting

confidence: 69%

mentioning

confidence: 99%

Rho’ing in and out of cells

2014

View full text Add to dashboard Cite

show abstract

“…Among several other cell surface proteins whose trafficking is affected by Nef are major histocompatibility class I molecules, which are downregulated by Nef to protect infected cells from recognition and lysis by cytotoxic T cells (10)(11)(12)(13)(14). Nef also modulates T cell antigen receptor signaling (15)(16)(17)(18)(19), interferes with T cell chemotaxis by inhibiting the remodeling of the actin cytoskeleton (20,21), and triggers the release of extracellular vesicles (22)(23)(24). Furthermore, the Nef proteins of certain simian immunodeficiency viruses counteract the restriction factor BST2 (25,26), which tethers budded virions to the cell surface (27).…”

mentioning

confidence: 99%

The Nef-Like Effect of Murine Leukemia Virus Glycosylated Gag on HIV-1 Infectivity Is Mediated by Its Cytoplasmic Domain and Depends on the AP-2 Adaptor Complex

Usami

Попов

Göttlinger

2014

J Virol

View full text Add to dashboard Cite

Human immunodeficiency virus type 1 (HIV-1) Nef enhances the infectivity of progeny virions. However, Nef is dispensable for the production of HIV-1 virions of optimal infectivity if the producer cells are superinfected with certain gammaretroviruses. In the case of the ecotropic Moloney murine leukemia virus (M-MLV), the Nef-like effect is mediated by the glycosylated Gag (glycoGag) protein. We now show that the N-terminal intracellular domain of the type II transmembrane protein glycoGag is responsible for its effect on HIV-1 infectivity. In the context of a fully active minimal M-MLV glycoGag construct, truncations of the cytoplasmic domain led to a near total loss of activity. Furthermore, the cytoplasmic domain of M-MLV glycoGag was fully sufficient to transfer the activity to an unrelated type II transmembrane protein. Although the intracellular region of glycoGag is relatively poorly conserved even among ecotropic and xenotropic MLVs, it was also fully sufficient for the rescue of nef-deficient HIV-1 when derived from a xenotropic virus. A mutagenic analysis showed that only a core region of the intracellular domain that exhibits at least some conservation between murine and feline leukemia viruses is crucial for activity. In particular, a conserved YXXL motif in the center of this core region was critical. In addition, expression of the 2 subunit of the AP-2 adaptor complex in virus producer cells was essential for activity. We conclude that the ability to enhance HIV-1 infectivity is a conserved property of the MLV glycoGag cytoplasmic domain and involves AP-2-mediated endocytosis. IMPORTANCEThe Nef protein of HIV-1 and the entirely unrelated glycosylated Gag (glycoGag) protein of a murine leukemia virus (MLV) similarly enhance the infectiousness of HIV-1 particles by an unknown mechanism. MLV glycoGag is an alternative version of the structural viral Gag protein with an extra upstream region that provides a cytosolic domain and a plasma membrane anchor. We now show for the first time that the cytosolic domain of MLV glycoGag contains all the information needed to enhance HIV-1 infectivity and that this function of the cytosolic domain is conserved despite limited sequence conservation. Within the cytosolic domain, a motif that resembles a cellular sorting signal is critical for activity. Furthermore, the enhancement of HIV-1 infectivity depends on an endocytic cellular protein that is known to interact with such sorting signals. Together, our findings implicate the endocytic machinery in the enhancement of HIV-1 infectivity by MLV glycoGag.

show abstract

“…After fusion of these microparticles with blood mononuclear cells, ADAM17-induced TNF-a release from the target cells. 42 It is conceivable that similar mechanisms of ADAM17 activation and release take place in active AAV. So far, we do not know which cell type is mainly responsible for enhanced release of ADAM17-containing microparticles into the vasculature in patients with AAV.…”

Section: Discussionmentioning

confidence: 99%

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

Bertram

Lovric

Engel

et al. 2015

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasmaderived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease.

show abstract

HIV Nef, Paxillin, and Pak1/2 Regulate Activation and Secretion of TACE/ADAM10 Proteases

Cited by 87 publications

References 51 publications

Rho’ing in and out of cells

Rho’ing in and out of cells

The Nef-Like Effect of Murine Leukemia Virus Glycosylated Gag on HIV-1 Infectivity Is Mediated by Its Cytoplasmic Domain and Depends on the AP-2 Adaptor Complex

Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis

Contact Info

Product

Resources

About