Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL, United States.
Department of Microbiology and Cell Science, University of Florida, Gainesville, FL, United States.
Front Immunol. 2022 Jun 21;13:902956. doi: 10.3389/fimmu.2022.902956. eCollection 2022.
Suppressors of Cytokine Signaling (SOCS) are intracellular proteins that negatively regulate the induction of cytokines. Amongst these, SOCS1 and SOCS3 are particularly involved in inhibition of various interferons. Several viruses have hijacked this regulatory pathway: by inducing SOCS1and 3 early in infection, they suppress the host immune response. Within the cell, SOCS1/3 binds and inhibits tyrosine kinases, such as JAK2 and TYK2. We have developed a cell penetrating peptide from the activation loop of the tyrosine kinase, JAK2 (residues 1001-1013), denoted as pJAK2 that acts as a decoy and suppresses SOCS1 and 3 activity. This peptide thereby protects against several viruses in cell culture and mouse models. Herein, we show that treatment with pJAK2 inhibited the replication and release of the beta coronavirus HuCoV-OC43 and reduced production of the viral RNA, as measured by RT-qPCR, Western blot and by immunohistochemistry. We confirmed induction of SOCS1 and 3 in rhabdomyosarcoma (RD) cells, and this induction was suppressed by pJAK2 peptide. A peptide derived from the C-terminus of IFNα (IFNα-C) also inhibited replication of OC43. Furthermore, IFNα-C plus pJAK2 provided more potent inhibition than either peptide alone. To extend this study to a pandemic beta-coronavirus, we determined that treatment of cells with pJAK2 inhibited replication and release of SARS-CoV-2 in Calu-3 cells. We propose that these peptides offer a new approach to therapy against the rapidly evolving strains of beta-coronaviruses.
细胞因子信号转导抑制因子（SOCS）是一种细胞内蛋白，可负向调节细胞因子的诱导。其中，SOCS1 和 SOCS3 特别参与多种干扰素的抑制。几种病毒已经劫持了这种调节途径：通过在感染早期诱导 SOCS1 和 3，它们抑制宿主免疫反应。在细胞内，SOCS1/3 结合并抑制酪氨酸激酶，如 JAK2 和 TYK2。我们从酪氨酸激酶 JAK2（残基 1001-1013）的激活环中开发了一种细胞穿透肽，称为 pJAK2，它作为诱饵并抑制 SOCS1 和 3 的活性。该肽因此可在细胞培养和小鼠模型中预防多种病毒。在此，我们表明 pJAK2 的处理抑制了β冠状病毒 HuCoV-OC43 的复制和释放，并通过 RT-qPCR、Western blot 和免疫组织化学减少了病毒 RNA 的产生。我们证实了 pJAK2 肽抑制横纹肌肉瘤（RD）细胞中 SOCS1 和 3 的诱导。来自 IFNα C 端的肽（IFNα-C）也抑制了 OC43 的复制。此外，IFNα-C 加 pJAK2 的抑制作用比单独使用任何一种肽都要强。为了将这项研究扩展到一种大流行的β冠状病毒，我们确定 pJAK2 的处理抑制了 Calu-3 细胞中 SARS-CoV-2 的复制和释放。我们提出这些肽为针对β冠状病毒不断进化的株提供了一种新的治疗方法。
