Characterization of E3 ligases involved in lysosomal sorting of the HIV-1 restriction factor BST2

Abstract

The cellular protein BST2 (also known as tetherin) acts as a major intrinsic antiviral protein that prevents the release of enveloped viruses by trapping nascent viral particles at the surface of infected cells. Viruses have evolved specific strategies to displace BST2 from viral budding sites in order to promote virus egress. In HIV-1, the accessory protein Vpu counters BST2 antiviral activity and promotes sorting of BST2 for lysosomal degradation. Vpu increases polyubiquitylation of BST2, a post-translation modification required for Vpu-induced BST2 downregulation, through recruitment of the E3 ligase complex SCF adaptors β-TrCP1 and β-TrCP2 (two isoforms encoded by BTRC and FBXW11, respectively). Herein, we further investigate the role of the ubiquitylation machinery in the lysosomal sorting of BST2. Using a small siRNA screen, we highlighted two additional regulators of BST2 constitutive ubiquitylation and sorting to the lysosomes: the E3 ubiquitin ligases NEDD4 and MARCH8. Interestingly, Vpu does not hijack the cellular machinery that is constitutively involved in BST2 ubiquitylation to sort BST2 for degradation in the lysosomes but instead promotes the recognition of BST2 by β-TrCP proteins. Altogether, our results provide further understanding of the mechanisms underlying BST2 turnover in cells.

Dengue virus non-structural protein 1 disrupts the TGF-β/Smad signaling 

“…Since NS1 does not possess ubiquitin function, it must do so by taking help from ubiquitins involved in TGF-β signaling. A handful of ubiquitins such as Smurf2 and CHIP/Stub1 are known to interact with Smad family proteins [15,[33][34][35]. Our results con rmed that these E3 ligases have different preferences during DENV replication and NS1 expression.…”

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

“…This finally results in the downregulation of surface levels of BST-2, thereby allowing normal rates of virion release in the presence of Vpu [ 77 , 85 , 137 , 138 ]. BST-2 is constitutively regulated by ubiquitination and lysosomal degradation mediated by the cellular E3 ubiquitin ligases March8 and NEDD4 (Neural precursor cell Expressed Developmentally Down-regulated protein 4) [ 139 ]. It is still a matter of debate however, whether Vpu also uses the endo-lysosomal system for BST-2 counteraction.…”

Dengue virus non structural protein 1 disrupts the TGF-β/Smad signaling by utilizing E3 ligase Smurf2

“…Next we found that these E3 ligases utilize the lysosomal pathway. Utilization of both protetosomal and lysosomal mediated pathway by E3 ligases in enveloped/RNA virus infection is well reported 19,30 . Utilization of such selective pathways during infection may be the one of the biological signatures of DENV pathogenesis.…”