Innate Sensing of HIV-1 Assembly by Tetherin Induces NFκB-Dependent Proinflammatory Responses

TY - JOUR

T1 - Innate Sensing of HIV-1 Assembly by Tetherin Induces NFκB-Dependent Proinflammatory Responses

AU - Galão, Rui Pedro

AU - Le Tortorec, Anna

AU - Pickering, Suzanne

AU - Kueck, Tonya

AU - Neil, Stuart J D

N1 - Copyright © 2012 Elsevier Inc. All rights reserved.

PY - 2012/11/15

Y1 - 2012/11/15

N2 - Antiviral proteins that recognize pathogen-specific or aberrantly located molecular motifs are perfectly positioned to act as pattern-recognition receptors and signal to the immune system. Here we investigated whether the interferon-induced viral restriction factor tetherin (CD317/BST2), which is known to inhibit HIV-1 particle release by physically tethering virions to the cell surface, has such a signaling role. We find that upon restriction of Vpu-defective HIV-1, tetherin acts as a virus sensor to induce NF kappa B-dependent proinflammatory gene expression. Signaling requires both tetherin's extracellular domain involved in virion retention and determinants in the cytoplasmic tail, including an endocytic motif, although signaling is independent of virion endocytosis. Furthermore, recruitment of the TNF-receptor-associated factor TRAF6 and activation of the mitogen-activated protein kinase TAK1 are critical for signaling. Human tetherin's ability to mediate efficient signaling may have arisen as a result of a five amino acid deletion that occurred in hominids after their divergence from chimpanzees.

AB - Antiviral proteins that recognize pathogen-specific or aberrantly located molecular motifs are perfectly positioned to act as pattern-recognition receptors and signal to the immune system. Here we investigated whether the interferon-induced viral restriction factor tetherin (CD317/BST2), which is known to inhibit HIV-1 particle release by physically tethering virions to the cell surface, has such a signaling role. We find that upon restriction of Vpu-defective HIV-1, tetherin acts as a virus sensor to induce NF kappa B-dependent proinflammatory gene expression. Signaling requires both tetherin's extracellular domain involved in virion retention and determinants in the cytoplasmic tail, including an endocytic motif, although signaling is independent of virion endocytosis. Furthermore, recruitment of the TNF-receptor-associated factor TRAF6 and activation of the mitogen-activated protein kinase TAK1 are critical for signaling. Human tetherin's ability to mediate efficient signaling may have arisen as a result of a five amino acid deletion that occurred in hominids after their divergence from chimpanzees.

KW - HUMAN-IMMUNODEFICIENCY-VIRUS

KW - INHIBITS HIV-1

KW - VPU PROTEIN

KW - RELEASE

KW - CELLS

KW - NEF

KW - UBIQUITINATION

KW - COUNTERACTION

KW - MECHANISM

KW - EVOLUTION

U2 - 10.1016/j.chom.2012.10.007

DO - 10.1016/j.chom.2012.10.007

M3 - Article

C2 - 23159053

SN - 1931-3128

VL - 12

SP - 633

EP - 644

JO - Cell Host and Microbe

JF - Cell Host and Microbe

IS - 5

ER -