Arrestin development: a role for β-arrestins in viral myocarditis

Each year, approximately 1 million individuals world-wide suffer from viral myocarditis, a major cause of sudden cardiac death.In an acute setting of viral myocarditis, the pathology is often self-limiting, and spontaneous recovery can occur.1 As a result, immunosuppressive therapy is often not prescribed unless there is a high risk.The need for such therapies can be arguably greater in chronic infection settings that result in dilated cardiomyopathy and heart failure, as the benefit of mitigating morbidity and mortality outweighs the risk of taking immunosuppressants. 1 A better understanding of the molecular mechanisms involved in regulating the inflammatory response that facilitates the progression versus resolution of myocarditis may provide novel targets for therapy.In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Lucero et.al. 2 investigated the role of β-arrestins in the inflammatory response to coxsackie B viral myocarditis.Coxsackie B virus is a cardiotropic virus often used in mouse models to study the viral myocarditis pathology.Using genetic models to delete β-arrestins, the authors identified a novel role of these scaffolding proteins in immune cell recruitment and myocyte apoptosis.The authors concluded that β-arrestins assist in modulating the progression of coxasackie B-mediated viral myocarditis through the cGAS-STING pathway by promoting the assembly or stability of the cGAS-dsDNA complex.A similar study using both murine and in vitro cellular models found that with viral infection, cells activate three main pathways including the cGAS-STING, the NF-κB, and MAPK pathways, however only β-arrestin 2 (βarr2) promoted activation of the cGAS-STING pathway.3 After infection with herpes simplex virus 1 (HSV-1) or vesicular stomatitis virus (VSV), βarr2 facilitated the production of IFN-β by targeting cGAS.Interestingly, when evaluating dimerization of STING, Zhang et al. found βarr2 deletion/knockdown decreased dimerization, but overexpression increased STING dimerization.3 This data supports the proposed hypothesis of Lucero et al. (2026) that β-arrestins is facilitating DNA-binding ability of cGAS.Whether β-arrestins directly regulate or recruit other enzymes to regulate cGAS activation is not known.