HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-golgi network-associated Lck signaling

• Verfasst von: Pan, Xiaoyu [VerfasserIn]
• Verfasst von: Rudolph, Jochen M. [VerfasserIn]
• Verfasst von: Abraham, Libin [VerfasserIn]
• Verfasst von: Habermann, Anja [VerfasserIn]
• Verfasst von: Haller, Claudia [VerfasserIn]
• Verfasst von: Krijnse-Locker, Jacomine [VerfasserIn]
• Verfasst von: Fackler, Oliver Till [VerfasserIn]
• Titel: HIV-1 Nef compensates for disorganization of the immunological synapse by inducing trans-golgi network-associated Lck signaling
• Verf.angabe: Xiaoyu Pan, Jochen M. Rudolph, Libin Abraham, Anja Habermann, Claudia Haller, Jacomine Krijnse-Locker, and Oliver T. Fackler
• Jahr: 2012
• Jahr des Originals: 2011
• Umfang: 12 S.
• Teil: volume:119
• Teil: year:2012
• Teil: number:3
• Teil: pages:786-797
• Teil: extent:12
• Fussnoten: Published online: November 28, 2011 ; Gesehen am 04.06.2018
• Titel Quelle: Enthalten in: Blood
• Ort Quelle: Washington, DC : American Society of Hematology, 1946
• Jahr Quelle: 2012
• Band/Heft Quelle: 119(2012), 3, Seite 786-797
• ISSN Quelle: 1528-0020
• DOI: doi:10.1182/blood-2011-08-373209
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1575952645

Abstract

The Nef protein of HIV-1 facilitates viral replication and disease progression in vivo. Nef disturbs the organization of immunological synapses between infected CD4+ T lymphocytes and antigen-presenting B-lymphocytes to interfere with TCR proximal signaling. Paradoxically, Nef enhances distal TCR signaling in infected CD4+ T lymphocytes, an effect thought to be involved in its role in AIDS pathogenesis. Using quantitative confocal microscopy and cell fractionation of Nef-expressing cells and HIV-1-infected primary human T lymphocytes, we found that Nef induces intracellular compartmentalization of TCR signaling to adjust TCR responses to antigenic stimulation. Nef reroutes kinase-active pools of the TCR signaling master switch Lck away from the plasma membrane (PM) to the trans-Golgi network (TGN), thereby preventing the recruitment of active Lck to the immunological synapse after TCR engagement and limiting signal initiation at the PM. Instead, Nef triggers Lck-dependent activation of TGN-associated Ras-Erk signaling to promote the production of the T lymphocyte survival factor IL-2 and to enhance virus spread. Overexpression of the Lck PM transporter Unc119 restores Nef-induced subversions of Lck trafficking and TCR signaling. Nef therefore hijacks Lck sorting to selectively activate TGN-associated arms of compartmentalized TCR signaling. By tailoring T-lymphocyte responses to antigenic stimulation, Nef optimizes the environment for HIV-1 replication.