Viral host range factors antagonize pathogenic SAMD9 and SAMD9L variants.

SAMD9 and SAMD9L encode homologous interferon-induced genes that can inhibit cellular translation as well as proliferation and can restrict viral replication. Gain-of-function (GoF) variants in these ancient, yet rapidly evolving genes are associated with life-threatening disease in humans. Potentially driving population sequence diversity, several viruses have evolved host range factors that antagonize cell-intrinsic SAMD9/SAMD9L function. Here, to gain insights into the molecular regulation of SAMD9/SAMD9L activity and to explore the prospect of directly counteracting the activity of pathogenic variants, we examined whether dysregulated activity of pathogenic SAMD9/SAMD9L variants can be modulated by the poxviral host range factors M062, C7 and K1 in a co-expression system. We established that the virally encoded proteins retain interactions with select SAMD9/SAMD9L missense GoF variants. Furthermore, expression of M062, C7 and K1 could principally ameliorate the translation-inhibiting and growth-restrictive effect instigated by ectopically expressed SAMD9/SAMD9L GoF variants, yet with differences in potency. K1 displayed the greatest potency and almost completely restored cellular proliferation and translation in cells co-expressing SAMD9/SAMD9L GoF variants. However, neither of the viral proteins tested could antagonize a truncated SAMD9L variant associated with severe autoinflammation. Our study demonstrates that pathogenic SAMD9/SAMD9L missense variants can principally be targeted through molecular interactions, opening an opportunity for therapeutic modulation of their activity. Moreover, it provides novel insights into the complex intramolecular regulation of SAMD9/SAMD9L activity.