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Review
. 2017 Oct 31;9(11):322.
doi: 10.3390/v9110322.

Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins

Affiliations
Review

Hijacking of the Ubiquitin/Proteasome Pathway by the HIV Auxiliary Proteins

Tanja Seissler et al. Viruses. .

Abstract

The ubiquitin-proteasome system (UPS) ensures regulation of the protein pool in the cell by ubiquitination of proteins followed by their degradation by the proteasome. It plays a central role in the cell under normal physiological conditions as well as during viral infections. On the one hand, the UPS can be used by the cell to degrade viral proteins, thereby restricting the viral infection. On the other hand, it can also be subverted by the virus to its own advantage, notably to induce degradation of cellular restriction factors. This makes the UPS a central player in viral restriction and counter-restriction. In this respect, the human immunodeficiency viruses (HIV-1 and 2) represent excellent examples. Indeed, many steps of the HIV life cycle are restricted by cellular proteins, some of which are themselves components of the UPS. However, HIV itself hijacks the UPS to mediate defense against several cellular restriction factors. For example, the HIV auxiliary proteins Vif, Vpx and Vpu counteract specific restriction factors by the recruitment of cellular UPS components. In this review, we describe the interplay between HIV and the UPS to illustrate its role in the restriction of viral infections and its hijacking by viral proteins for counter-restriction.

Keywords: APOBEC; BST2/Tetherin; HIV; March8; SAMHD1; TRIM5α; proteasome; restriction factors; ubiquitin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the ubiquitin-proteasome system. (A) Transfer of ubiquitin from the ubiquitin-activating enzyme E1 to the ubiquitin-conjugating enzyme E2 followed by its transfer onto the target protein X by the ubiquitin ligase E3. The broken line symbolizes the thiol-ester bond; (B) the 26S proteasome, composed of the 20S barrel and two 19S lids. The ubiquitinated target protein X is recognized by one of the lids and translocated through the barrel where it is degraded by the proteases located on the inside of the β-rings.
Figure 2
Figure 2
Schematic representation of the HIV-1 life cycle. The main HIV-1 restriction factors and the viral auxiliary proteins that counteract these factors (represented by T bars) are highlighted in red and blue boxes, respectively. See text for a description of the different steps of the life cycle.
Figure 3
Figure 3
Restriction of HIV by TRIM5α and March8. (A,B) Schematic representation of the main domains of (A) the TRIM5α and (B) March8 proteins. Black boxes correspond to transmembrane domains (TM). Amino acid positions of the beginning and end of the domains as well as the total length of the proteins are indicated; (C) mechanism of TRIM5α restriction. The dimeric TRIM5α (red) recognizes the viral capsid and ① induces the proteasomal degradation of the capsid (blue), the integrase (yellow) and itself, leading to premature decapsidation of viral RNA. ② TRIM5α also blocks integration of the provirus (red T bar) and ③ induces activation of AP1 and NFκB pathways; (D) March8 (red) mediates intracellular retention of envelope proteins (Env, brown), leading to reduced Env incorporation into virions, thereby decreasing infectivity.
Figure 4
Figure 4
Restriction of HIV by APOBEC3G and counteraction by Vif. (A,B) Schematic representation of the main domains of (A) the APOBEC3G and (B) Vif proteins. Amino acid positions of the beginning and end of the domains as well as the total length of the proteins are indicated; (C) the mechanism of APOBEC3G restriction and Vif counteraction. APOBEC3G (red) is incorporated into virions and induces hypermutations of the provirus leading either to its degradation or production of truncated viral proteins. Vif (blue) decreases A3G transcription ①, inhibits its translation ② (Red T bar) and induces its degradation by the proteasome ③.
Figure 5
Figure 5
Restriction of HIV by SAMHD1 and counteraction by Vpx. (A,B) Schematic representation of the main domains of (A) SAMHD1 and (B) Vpx. The nuclear localization signal (NLS) is indicated in red. Amino acid positions of the beginning and end of the domains as well as the total length of the proteins are indicated; (C) the mechanism of SAMHD1 restriction and Vpx counteraction. Tetrameric SAMHD1 (red) hydrolyzes dNTPs, leading to a block of reverse transcription of the viral genome. Vpx (blue) induces SAMHD1 ubiquitination followed by its degradation by the proteasome.
Figure 6
Figure 6
Restriction of HIV by BST-2 and counteraction by Vpu. (A,B) Schematic representation of the main domains of (A) the BST-2 and (B) Vpu proteins. Black boxes indicate transmembrane domains (TM). The glycosyl-phosphatidylinositol (GPI) modification at the C-terminal end of BST-2 is indicated. Amino acid positions of the beginning and end of the domains as well as the total length of the proteins are indicated; (C) mechanism of BST-2 restriction and Vpu counteraction. BST-2 tethers virions to the plasma membrane, thereby hindering their dissemination. Vpu sequesters BST-2 away from virion budding sites either at the plasma membrane ① or in intracellular compartments ②. Vpu can also induce BST-2 degradation in the endo-lysosomal pathway ③.

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