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

J Virol. 2022 Feb 23;96(4):e0168821. doi: 10.1128/JVI.01688-21. Epub 2021 Dec 8.

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 completely clear. In this study, we focused on the effect of HHV-6A U4 gene function on Aβ expression. Coexpression of HHV-6A U4 with amyloid precursor protein (APP) resulted in inhibition of ubiquitin-mediated proteasomal degradation of APP. Consequently, accumulation of β-amyloid peptide (Aβ), insoluble neurofibrillary tangles, and loss of neural cells may occur. Immunoprecipitation coupled with 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 the inhibition of APP ubiquitin modification and clearance. Finally, this leads to an increase in APP expression and Aβ deposition, which are the hallmarks of AD. These findings provide novel evidence for the etiological hypothesis of AD, which can contribute to the further analysis of the role of HHV-6A 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 amyloid precursor protein (APP) degradation. U4 protein interacts with CRLs (cullin-RING E3 ubiquitin-protein ligases), which is also responsible for APP degradation. We propose a model in which 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.

Keywords: APP; HHV-6A; U4; amyloid precursor protein; human herpesvirus 6A; ubiquitination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Cell Line
  • Cullin Proteins / metabolism
  • DNA-Binding Proteins / metabolism
  • Gene Expression
  • Herpesvirus 6, Human / genetics
  • Herpesvirus 6, Human / metabolism*
  • Humans
  • Proteasome Endopeptidase Complex / metabolism*
  • Protein Binding
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • Viral Proteins / genetics
  • Viral Proteins / metabolism*

Substances

  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • CUL4B protein, human
  • Cullin Proteins
  • DDB1 protein, human
  • DNA-Binding Proteins
  • Ubiquitin
  • Viral Proteins
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex