Human Herpesvirus 6A U4 Inhibits Proteasomal Degradation of the Amyloid Precursor Protein

Abstract

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.

New Insights into the Molecular Interplay between Human Herpesviruses and Alzheimer’s Disease—A Narrative Review

“…The HHV 6A infection of microglial cells also promoted Aβ accumulation, as well as tau phosphorylation [ 76 ]. Recently, HHV 6A U4 protein was found to interact with cullin-RING E3 ubiquitin-protein ligases [ 77 ], a highly polymorphic E3 collection composed of a cullin backbone onto which carriers of activated ubiquitin and a diverse assortment of adaptors are bound to recruit appropriate substrates for ubiquitylation [ 78 ]. The above research findings led to the hypothesis that HHV 6A U4 protein competes with APP for binding to E3 ubiquitin ligase, and thus it prevents APP proteasomal degradation leading to increased APP expression and Aβ deposition.…”

The viral hypothesis in Alzheimer’s disease: SARS-CoV-2 on the cusp

“…HHV6 uses the olfactory pathway as a route to the CNS ( Harberts et al, 2011 ). HHV6A infection may be associated with AD ( Tang et al, 2022 ). Human herpesvirus 6 is frequently detected in AD and healthy older brains.…”

Bis-tridentate Iridium(III) Complex with the N-Heterocyclic Carbene Ligand as a Novel Efficient Electrochemiluminescence Emitter for the Sandwich Immunoassay of the HHV-6A Virus

“…Human herpesvirus type 6A (HHV-6A) is a member of the herpes B virus family and widely exists in the world population, especially in young children. , In the case of impaired immunity, HHV-6A may activate and cause a series of immune and neurological diseases, such as fever and encephalitis, causing serious health hazards to humans. , At present, the mainstream detection of HHV-6A is real-time polymerase chain reaction (PCR), which transcribe viral DNA in real-time samples such as blood and body fluids for quantitative detection. − However, PCR analysis is time-consuming and requires extensive sample processing, and it can only amplify known DNA sequences. The equipment and instruments of PCR are all expensive and it also requires professional technicians . Therefore, there is an urgent need for a unique, sensitive, and convenient detection method to realize the scientific detection of HHV-6A.…”