HIV-1 has evolved effective strategies to evade the host immune response, most of which are mediated by a set of viral “accessory” proteins: VIF, VPR, VPU and NEF. The majority of these proteins interfere with multiple intracellular pathways by usurping the cellular Cullin Ring Ubiquitin Ligase systems (CRLs) and by promoting the ubiquitination and the degradation of host antiviral factors. The HIV-1 accessory protein VPU interacts with the Cullin1 complex to enhance the degradation of the transmembrane protein BST2, a factor involved in the retention of viral particles and the inhibition of viral spread. On the other hand, VPR associates to the Cullin4 Complex to stimulate the degradation of the Uracyl DNA Glycosylase UNG2, a protein that, in addition to its role in the progression from S to G2 phase, is able to cause mutations in the viral genome. Recent findings demonstrate that the proautophagic protein AMBRA1 interacts with multiple Cullin RING complexes and regulates their activity (Antonioli et al., 2014), including both Cullin 4 and Cullin 1 adaptors. Moreover, AMBRA1 was identified among VIF interactors in a HIV proteomic study, suggesting the possible involvement of AMBRA1 in the activity of different HIV-1 accessory proteins. In this work, we found that AMBRA1, in addition to VIF, it also interacts with other two HIV-1 accessory proteins: VPR and VPU. Moreover, we show that the HIV-1 accessory proteins VPR and VPU promote the interaction of AMBRA1 with Cul4 and Cullin1 complexes, respectively. Importantly, AMBRA1 silencing impairs HIV-induced degradation of both UNG2 and BST2. Finally, we show that VPU expression results in increased basal and starvation-induced autophagy, and induces the colocalization of BST2 with LC3 positive vesicles, which mediate its delivery to the lysosomes. Altogether, these data provide new insights about the role of the proautophagic protein AMBRA1 and on how HIV-1 exploits the autophagy process for its life cycle, further highlighting the complex interplay between autophagy and the innate immune response.
(2013). Functional characterization of the interaction between the HIV accessory proteins VPU and VPR and the proautophagic protein AMBRA1.
|Titolo:||Functional characterization of the interaction between the HIV accessory proteins VPU and VPR and the proautophagic protein AMBRA1|
|Data di pubblicazione:||2013|
|Corso di dottorato:||Biologia cellulare e molecolare|
|Settore Scientifico Disciplinare:||Settore BIO/12|
|Tipologia:||Tesi di dottorato|
|Citazione:||(2013). Functional characterization of the interaction between the HIV accessory proteins VPU and VPR and the proautophagic protein AMBRA1.|
|Appare nelle tipologie:||07 - Tesi di dottorato|