Tetherin and its viral antagonists

Abstract

Restriction factors comprise an important layer of host defense to fight against viral infection. Some restriction factors are constitutively expressed whereas the majority is induced by interferon to elicit innate immunity. In addition to a number of well-characterized interferon-inducible antiviral factors such as RNaseL/OAS, ISG15, Mx, PKR, and ADAR, tetherin (BST-2/CD317/HM1.24) was recently discovered to block the release of enveloped viruses from the cell surface, which is regarded as a novel antiviral mechanism induced by interferon. Here, we briefly review the history of tetherin discovery, discuss how tetherin blocks virus production, and highlight the viral countermeasures to evade tetherin restriction.

Fig. 1

Antiviral mechanism of tetherin. a Tetherin localizes to the virus budding site and incorporates into the viral membrane. Tetherin exerts its antiviral action by tethering viral particles to the cell and to each other. Further, tetherin inhibits protease-mediated viral maturation of released viral particles. b, c Models of molecular tethering mechanism. Tetherin homodimers are likely oriented in parallel. Tetherin links viral particles to cells by insertion of one terminus into the virion membrane, while the other is located in the cellular membrane (b), or tetherin may link viral particles and cells via dimerization of the ectodomains of monomers with both termini inserted in either the virion membrane or the cellular membrane

Fig. 2

Models of tetherin and Vpu transmembrane domains. The transmembrane domains of human tetherin (left) and HIV-1 Vpu (right) are illustrated in regard to their orientation in the membrane. Amino acids of the tetherin transmembrane known to impact on the interaction without abruption of tetherin function are highlighted in blue and indicated left to the model; amino acids are selected according to Gupta et al. (2009a), McNatt et al. (2009), and Rong et al. (2009). Amino acids that are involved in tetherin downmodulation from the cell surface are highlighted in yellow on the Vpu transmembrane model (Vigan and Neil 2010). Models were created with PyMol software on the basis of the sequences of human tetherin (GenBank ID NP_004326.1) and HIV-1 Vpu from viral clone pNL_4-3 (GenBank ID AAK08488.1)

Fig. 3

Crystal structure of tetherin ectodomain. Shown are the crystal structures of a tetherin dimer (top) and tetramer (bottom). The disulfide bond building cysteine residues C₅₃C₆₃C₉₁ are highlighted in blue (top and bottom); N-glycosylation sites N₆₅N₉₂ are presented in purple (top). Structures are based on the X-ray crystallography data from Schubert et al. (2010) (PDB ID: 3NWH) and were created using PyMol software. Structures of the ectodomains were created using PyMol software

Fig. 4

Illustration of viral counter measures against tetherin. The normal cellular trafficking of tetherin is depicted from the endoplasmic reticulum (ER) to the Golgi apparatus, to the plasma membrane, and then through recycling endosomes. This trafficking is interrupted by several viral proteins that have been identified to antagonize tetherin. Vpu may sequester tetherin at the TGN or recruit β-TrCP to ubiquitinate tetherin and target it for degradation via the lysosomal or proteasomal pathway. Nef interacts with the cytoplasmic tail of tetherin and triggers tetherin downregulation from the cell surface. SIV/HIV-2/Ebola envelope proteins may sequester tetherin at the TGN/perinuclear regions. K5 ubiquitinates tetherin and causes tetherin degradation in lysosomes

Fig. 5

Sequence alignment of primate tetherins. Aligned are tetherin amino acid sequences of selected simians from the Old World monkey lineage (SMN Sooty mangabey; AGM African green monkey; MAC Rhesus macaque) and hominid lineage (CPZ chimpanzee; gorilla; human). Highlighted are the domains that determine sensitivity to Nef (yellow), the cysteines that are involved in tetherin dimerization via disulfide bonds (blue), and the GPI anchor attachment site (green). Alignment was created using ClustalX software; sequence files are derived from GenBank: SMN, ADI58600.1; AGM, ADI58599.1; MAC, ADI58602.1; CPZ, ADI58593.1; Gorilla, ADI58594.1; Human, NP_004326.1