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Studying the Interactions of U24 from HHV-6 in Order to Further Elucidate Its Potential Role in MS
Keng-Shuo Pi1, Daria Bortolotti2, Yurou Sang1,3
1Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
Abstract:
A number of studies have suggested that human herpesvirus 6A (HHV-6A) may play a role in multiple sclerosis (MS). Three possible hypotheses have been investigated: (1) U24 from HHV-6A (U24-6A) mimics myelin basic protein (MBP) through analogous phosphorylation and interaction with Fyn-SH3; (2) U24-6A affects endocytic recycling by binding human neural precursor cell (NPC) expressed developmentally down-regulated protein 4-like WW3* domain (hNedd4L-WW3*); and (3) MS patients who express Killer Cell Immunoglobulin Like Receptor 2DL2 (KIR2DL2) on natural killer (NK) cells are more susceptible to HHV-6 infection. In this contribution, we examined the validity of these propositions by investigating the interactions of U24 from HHV-6B (U24-6B), a variant less commonly linked to MS, with Fyn-SH3 and hNedd4L-WW3* using heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) titrations and isothermal titration calorimetry (ITC). In addition, the importance of phosphorylation and the specific role of U24 in NK cell activation in MS patients were examined. Overall, the findings allowed us to shed light into the models linking HHV-6 to MS and the involvement of U24.
Insights
Human herpesvirus 6B (HHV-6B) U24 protein interactions with Fyn-SH3 and hNedd4L-WW3* were investigated. This research clarifies the role of HHV-6 in multiple sclerosis (MS) pathogenesis and U24 involvement.
Area of Science:
- Virology
- Neuroimmunology
- Molecular Biology
Background:
- Human herpesvirus 6A (HHV-6A) is implicated in multiple sclerosis (MS) pathogenesis.
- Proposed mechanisms include molecular mimicry of myelin basic protein (MBP) by HHV-6A U24 and effects on endocytic recycling.
- Natural killer (NK) cell receptor KIR2DL2 expression in MS patients is linked to HHV-6 susceptibility.
Purpose of the Study:
- To investigate the interactions of human herpesvirus 6B (HHV-6B) U24 protein with Fyn-SH3 and hNedd4L-WW3*.
- To examine the role of phosphorylation and U24 in NK cell activation in MS patients.
- To evaluate the validity of proposed HHV-6 mechanisms in MS.
Main Methods:
- Heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) titrations.
- Isothermal titration calorimetry (ITC).
- Analysis of phosphorylation and NK cell activation.
Main Results:
- HHV-6B U24 interactions with Fyn-SH3 and hNedd4L-WW3* were characterized.
- The study provided insights into the molecular mechanisms linking HHV-6 to MS.
- The specific role of U24 in NK cell activation was explored.
Conclusions:
- The findings contribute to understanding the molecular basis of HHV-6 involvement in MS.
- This research clarifies the function of U24 in the context of neuroinflammation.
- Further investigation into HHV-6 variants and MS pathogenesis is warranted.
