Human herpesvirus 6A U4 inhibits proteasomal degradation of amyloid precursor protein

Human herpesvirus 6 (HHV-6) belongs to the betaherpesvirus subfamily and is divided into two distinct species, HHV-6A and HHV-6B. HHV-6 can infect nerve cells and is associated with a variety of nervous system diseases. Recently, the association of HHV-6A infection with Alzheimer's disease (AD) has been suggested. The main pathological phenomena of AD are the accumulation of β-amyloid (Aβ), neurofibrillary tangles, and neuroinflammation, however, the specific molecular mechanism of pathogenesis of AD is not fully clear. In this study, we focused on the effect of HHV-6A U4 gene function on Aβ expression. Co-expression of HHV-6A U4 with APP resulted in inhibition of ubiquitin-mediated proteasomal degradation of amyloid precursor protein (APP). Consequently, accumulation of β-amyloid peptide (Aβ), insoluble neurofibrillary tangles, and loss of neural cells may occur. Immunoprecipitation coupled to mass spectrometry (IP-MS) showed that HHV-6A U4 protein interacts with E3 ubiquitin ligase composed of DDB1 and Cullin 4B which is also responsible for APP degradation. We hypothesize that HHV-6A U4 protein competes with APP for binding to E3 ubiquitin ligase, resulting in inhibition of APP ubiquitin modification and clearance. Finally, this is leading to the increase of APP expression and Aβ deposition, which is the hallmark of AD. These findings provide novel evidence for the etiological hypothesis of AD that can contribute to the further analysis of HHV-6A role in AD. IMPORTANCE The association of HHV-6A infection with Alzheimer’s disease has attracted increasing attention, although its role and molecular mechanism remain to be established. Our results here indicate that HHV-6A U4 inhibits APP (amyloid precursor protein) degradation. U4 protein interacts with CRLs (Cullin-RING E3 ubiquitin-protein ligases) which is also responsible for APP degradation. We propose a model that U4 competitively binds to CRLs with APP, resulting in APP accumulation and Aβ generation. Our findings provide new insights into the etiological hypothesis of HHV-6A in AD that can help further analyses.