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

doi:10.3390/v14112384

Studying the Interactions of U24 from HHV-6 in Order to Further Elucidate Its Potential Role in MS

Viruses. 2022 Oct 28;14(11):2384. doi: 10.3390/v14112384.

Authors

Affiliations

¹ Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
² Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy.
³ Faculty of Health Sciences, Simon Fraser University, 8888 University Drive, Burnaby, BC V5A 1S6, Canada.
⁴ Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliero-Universitaria S. Anna, 44121 Ferrara, Italy.
⁵ Department of Neuroscience and Rehabilitation, Division of Neurology, "Sant'Anna" University-Hospital, 44121 Ferrara, Italy.
⁶ Michael Smith Laboratories and Department of Chemical and Biological Engineering, University of British Columbia, 2185 East Mall, Vancouver, BC V6T 1Z4, 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.

Keywords: Fyn-SH3; Killer Cell Immunoglobulin Like Receptor 2DL2; Nedd4L; Roseolovirus; human herpes virus; multiple sclerosis; natural killer cells; phosphorylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Herpesvirus 6, Human* / physiology
Humans
Multiple Sclerosis*
Nuclear Magnetic Resonance, Biomolecular
Phosphorylation
Roseolovirus Infections*

Grants and funding

Funding to S.K.S. from the Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-03831) and from the University of British Columbia Faculty of Science (STAIR) are gratefully acknowledged. Funding to R.R. is from the FISM–Fondazione Italiana Sclerosi Multipla onlus grant no° Cod 2019/R-Single/004 and is gratefully acknowledged.