Sulforaphane Reduces SAMHD1 Phosphorylation To Protect Macrophages from HIV-1 Infection
Sulforaphane Reduces SAMHD1 Phosphorylation To Protect Macrophages from HIV-1 Infection
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DOI：
10.1128/jvi.01187-22
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发表时间：
2022-11-15
影响因子：
5.4
通讯作者：
de Noronha, Carlos M. C.
中科院分区：
文献类型：
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作者：
Sharifi, H. John;Paine, Dakota N.;de Noronha, Carlos M. C.
细胞蛋白SAMHD 1对于DNA修复、抑制LINE元件、控制脱氧核苷三磷酸（dNTP）浓度、维持HIV-1潜伏期和防止过度的I型干扰素应答是重要的。SAMHD 1也是HIV-1和其他重要病毒病原体的有效抑制剂。感染限制部分是由于SAMHD 1的脱氧核苷三磷酸酶（dNTPase-independent mechanism）活性，但也通过dNTPase-independent mechanism介导，该机制已被描述但尚未探索。SAMHD 1在苏氨酸592（T592）处的磷酸化控制其许多功能。逆转录病毒的限制，无论dNTR的活性，是连接到非磷酸化的T592。萝卜硫素（SFN）是一种异硫氰酸酯，通过动员转录因子和抗氧化反应调节因子Nrf 2来保护巨噬细胞免受HIV感染。在这里，我们表明SFN和其他临床相关的Nrf 2动员剂减少SAMHD 1 T592磷酸化，以保护巨噬细胞免受HIV-1的侵害。我们进一步表明，SFN，通过Nrf 2，触发人类单核细胞衍生的巨噬细胞的细胞周期控制蛋白p21的上调，有助于SAMHD 1激活。我们还提供了支持SFN通过减少磷酸化作用促进SAMHD 1活化的另一种潜在的氧化还原依赖性机制的数据。这项工作建立了使用外源性Nrf 2动员剂作为一种新的方式来研究病毒的限制SAMHD 1和突出的Nrf 2途径作为一个潜在的目标，为治疗控制SAMHD 1细胞和抗病毒functions.IMPORTANCE在这里，我们表明，第一次，治疗巨噬细胞与Nrf 2动员剂，已知的激活剂的抗氧化反应，增加在592位没有调节磷酸的SAMHD 1的分数。我们证明这减少了HIV-1对巨噬细胞的感染。磷酸化的SAMHD 1对于DNA修复、LINE元件的抑制、HIV-1在潜伏状态的维持和过度I型干扰素应答的预防是重要的，而未磷酸化的SAMHD 1阻断HIV感染。SAMHD 1影响许多病毒并参与各种癌症，因此了解它如何工作以及如何调节对治疗方法的发展具有广泛的意义。氧化还原调节治疗剂已经在临床上使用或正在研究用于治疗许多病症。因此，了解氧化还原修饰剂对控制SAMHD 1磷酸化的影响是重要的微生物学和beyond.在这里，我们表明，第一次，治疗巨噬细胞与Nrf 2动员剂，已知的抗氧化反应的激活剂，增加SAMHD 1的分数没有调节磷酸盐在位置592。我们证明这减少了HIV-1对巨噬细胞的感染。
The cellular protein SAMHD1 is important for DNA repair, suppressing LINE elements, controlling deoxynucleoside triphosphate (dNTP) concentrations, maintaining HIV-1 latency, and preventing excessive type I interferon responses. SAMHD1 is also a potent inhibitor of HIV-1 and other significant viral pathogens. Infection restriction is due in part to the deoxynucleoside triphosphatase (dNTPase) activity of SAMHD1 but is also mediated through a dNTPase-independent mechanism that has been described but not explored. The phosphorylation of SAMHD1 at threonine 592 (T592) controls many of its functions. Retroviral restriction, irrespective of dNTPase activity, is linked to unphosphorylated T592. Sulforaphane (SFN), an isothiocyanate, protects macrophages from HIV infection by mobilizing the transcription factor and antioxidant response regulator Nrf2. Here, we show that SFN and other clinically relevant Nrf2 mobilizers reduce SAMHD1 T592 phosphorylation to protect macrophages from HIV-1. We further show that SFN, through Nrf2, triggers the upregulation of the cell cycle control protein p21 in human monocyte-derived macrophages to contribute to SAMHD1 activation. We additionally present data that support another, potentially redox-dependent mechanism employed by SFN to contribute to SAMHD1 activation through reduced phosphorylation. This work establishes the use of exogenous Nrf2 mobilizers as a novel way to study virus restriction by SAMHD1 and highlights the Nrf2 pathway as a potential target for the therapeutic control of SAMHD1 cellular and antiviral functions.IMPORTANCE Here, we show, for the first time, that the treatment of macrophages with Nrf2 mobilizers, known activators of antioxidant responses, increases the fraction of SAMHD1 without a regulatory phosphate at position 592. We demonstrate that this decreases infection of macrophages by HIV-1. Phosphorylated SAMHD1 is important for DNA repair, the suppression of LINE elements, the maintenance of HIV-1 in a latent state, and the prevention of excessive type I interferon responses, while unphosphorylated SAMHD1 blocks HIV infection. SAMHD1 impacts many viruses and is involved in various cancers, so knowledge of how it works and how it is regulated has broad implications for the development of therapeutics. Redox-modulating therapeutics are already in clinical use or under investigation for the treatment of many conditions. Thus, understanding the impact of redox modifiers on controlling SAMHD1 phosphorylation is important for many areas of research in microbiology and beyond.Here, we show, for the first time, that the treatment of macrophages with Nrf2 mobilizers, known activators of antioxidant responses, increases the fraction of SAMHD1 without a regulatory phosphate at position 592. We demonstrate that this decreases infection of macrophages by HIV-1.