Studying the Interactions of U24 from HHV-6 in Order to Further Elucidate Its Potential Role in MS
Keng-Shuo Pi,
Daria Bortolotti,
Yurou Sang,
Giovanna Schiuma,
Silvia Beltrami,
Sabrina Rizzo,
Alessandra Bortoluzzi,
Eleonora Baldi,
A. Louise Creagh,
Charles A. Haynes,
Roberta Rizzo,
Suzana K. Straus
Affiliations
Keng-Shuo Pi
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
Daria Bortolotti
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy
Yurou Sang
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
Giovanna Schiuma
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy
Silvia Beltrami
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy
Sabrina Rizzo
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy
Alessandra Bortoluzzi
Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliero-Universitaria S. Anna, 44121 Ferrara, Italy
Eleonora Baldi
Department of Neuroscience and Rehabilitation, Division of Neurology, “Sant’Anna” University-Hospital, 44121 Ferrara, Italy
A. Louise Creagh
Michael Smith Laboratories and Department of Chemical and Biological Engineering, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada
Charles A. Haynes
Michael Smith Laboratories and Department of Chemical and Biological Engineering, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, Canada
Roberta Rizzo
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy
Suzana K. Straus
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
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.
