Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity.
Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity.
复制标题
DOI：
10.1074/jbc.ra120.015138
复制
发表时间：
2020-12-25
期刊：
影响因子：
--
通讯作者：
Brenner C
中科院分区：
文献类型：
--
作者：
Heer CD;Sanderson DJ;Voth LS;Alhammad YMO;Schmidt MS;Trammell SAJ;Perlman S;Cohen MS;Fehr AR;Brenner C
聚（ADP-核糖）聚合酶 (PARP) 超家族成员使用 NAD 作为 ADPR 的来源，将单个 ADP-核糖 (ADPR) 或 ADPR 单元链与蛋白质共价连接。虽然众所周知的聚（ADP-核糖基化）（PARylating）PARP 主要在 DNA 损伤反应中发挥作用，但许多非经典的单（ADP-核糖基化）（MARylating）PARP 与细胞抗病毒反应有关。我们最近证明，在感染鼠肝炎病毒（MHV）（一种模型冠状病毒）后，几种 PARP 会出现强劲上调。在这里，我们发现 SARS-CoV-2 感染显着上调 MARylating PARP，并诱导编码酶的基因表达，以挽救烟酰胺 (NAM) 和烟酰胺核苷 (NR) 的 NAD 合成，同时下调其他 NAD 生物合成途径。我们表明，PARP10 的过表达足以抑制细胞 NAD，并且转录诱导酶 PARP7、PARP10、PARP12 和 PARP14 的活性受到细胞 NAD 的限制，并且可以通过 NAD 合成的药理学激活来增强。我们进一步证明，MHV 感染会诱导对宿主细胞 NAD+ 和 NADP+ 的严重攻击。最后，我们发现 NAMPT 激活、NAM 和 NR 显着降低了对 PARP 活性敏感的 MHV 的复制。这些数据表明，非经典 PARP 同工酶活性的抗病毒活性受到 NAD 可用性的限制，而提高 NAD 水平的营养和药物干预措施可能会增强对冠状病毒的先天免疫力。
Poly(ADP-ribose) polymerase (PARP) superfamily members covalently link either a single ADP-ribose (ADPR) or a chain of ADPR units to proteins using NAD as the source of ADPR. Although the well-known poly(ADP-ribosylating) (PARylating) PARPs primarily function in the DNA damage response, many noncanonical mono(ADP-ribosylating) (MARylating) PARPs are associated with cellular antiviral responses. We recently demonstrated robust up-regulation of several PARPs following infection with murine hepatitis virus (MHV), a model coronavirus. Here we show that SARS-CoV-2 infection strikingly up-regulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while down-regulating other NAD biosynthetic pathways. We show that overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis. We further demonstrate that infection with MHV induces a severe attack on host cell NAD+ and NADP+. Finally, we show that NAMPT activation, NAM, and NR dramatically decrease the replication of an MHV that is sensitive to PARP activity. These data suggest that the antiviral activities of noncanonical PARP isozyme activities are limited by the availability of NAD and that nutritional and pharmacological interventions to enhance NAD levels may boost innate immunity to coronaviruses.