Institute of Biochemistry, Kiel University, Rudolf-Höber-Str. 1, D-24118, Kiel, Germany.
Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Exp Cell Res. 2023 Apr 15;425(2):113541. doi: 10.1016/j.yexcr.2023.113541. Epub 2023 Mar 7.
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.
SAMD9 和 SAMD9L 编码同源的干扰素诱导基因，这些基因可以抑制细胞翻译、增殖，并限制病毒复制。这些古老但快速进化的基因中的功能获得性（Gain-of-Function，GoF）变体与人类危及生命的疾病有关。几种病毒为了拮抗细胞内固有 SAMD9/SAMD9L 功能，已经进化出宿主范围因子，从而导致潜在的种群序列多样性。为了深入了解 SAMD9/SAMD9L 活性的分子调控机制，并探索直接对抗致病变异体活性的可能性，我们研究了失调的致病性 SAMD9/SAMD9L 变体的活性是否可以在共表达系统中被痘病毒宿主范围因子 M062、C7 和 K1 调节。我们发现，病毒编码的蛋白仍然与 SAMD9/SAMD9L 错义 GoF 变体发生相互作用。此外，M062、C7 和 K1 的表达可以主要减轻由异位表达的 SAMD9/SAMD9L GoF 变体引发的翻译抑制和生长限制效应，但在效力上存在差异。K1 显示出最强的效力，几乎完全恢复了共表达 SAMD9/SAMD9L GoF 变体的细胞增殖和翻译。然而，测试的病毒蛋白均不能拮抗与严重自身炎症相关的截断 SAMD9L 变体。我们的研究表明，致病性 SAMD9/SAMD9L 错义变体可以通过分子相互作用主要作为靶点，为其活性的治疗性调节开辟了机会。此外，它为 SAMD9/SAMD9L 活性的复杂分子内调控提供了新的见解。
