Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
Int J Mol Sci. 2024 Jul 10;25(14):7550. doi: 10.3390/ijms25147550.
PARK7, also known as DJ-1, plays a critical role in protecting cells by functioning as a sensitive oxidation sensor and modulator of antioxidants. DJ-1 acts to maintain mitochondrial function and regulate transcription in response to different stressors. In this study, we showed that cell lines vary based on their antioxidation potential under basal conditions. The transcriptome of HEK293 cells was tested following knockdown (KD) of DJ-1 using siRNAs, which reduced the DJ-1 transcripts to only 12% of the original level. We compared the expression levels of 14k protein-coding transcripts and 4.2k non-coding RNAs relative to cells treated with non-specific siRNAs. Among the coding genes, approximately 200 upregulated differentially expressed genes (DEGs) signified a coordinated antiviral innate immune response. Most genes were associated with the regulation of type 1 interferons (IFN) and the induction of inflammatory cytokines. About a quarter of these genes were also induced in cells treated with non-specific siRNAs that were used as a negative control. Beyond the antiviral-like response, 114 genes were specific to the KD of DJ-1 with enrichment in RNA metabolism and mitochondrial functions. A smaller set of downregulated genes (58 genes) was associated with dysregulation in membrane structure, cell viability, and mitophagy. We propose that the KD DJ-1 perturbation diminishes the protective potency against oxidative stress. Thus, it renders the cells labile and responsive to the dsRNA signal by activating a large number of genes, many of which drive apoptosis, cell death, and inflammatory signatures. The KD of DJ-1 highlights its potency in regulating genes associated with antiviral responses, RNA metabolism, and mitochondrial functions, apparently through alteration in STAT activity and downstream signaling. Given that DJ-1 also acts as an oncogene in metastatic cancers, targeting DJ-1 could be a promising therapeutic strategy where manipulation of the DJ-1 level may reduce cancer cell viability and enhance the efficacy of cancer treatments.
PARK7，也称为 DJ-1，在作为敏感的氧化传感器和抗氧化剂调节剂发挥作用时，对保护细胞起着至关重要的作用。DJ-1 作用是维持线粒体功能并调节转录，以响应不同的应激源。在这项研究中，我们表明细胞系根据其在基础条件下的抗氧化潜力而有所不同。使用 siRNA 敲低（KD）DJ-1 后，测试了 HEK293 细胞的转录组，这将 DJ-1 转录物降低到原始水平的 12%。我们比较了用非特异性 siRNA 处理的细胞中 14k 蛋白编码转录物和 4.2k 非编码 RNA 的表达水平。在编码基因中，大约 200 个上调的差异表达基因（DEG）标志着协调的抗病毒先天免疫反应。大多数基因与 1 型干扰素（IFN）的调节和炎症细胞因子的诱导有关。大约四分之一的这些基因也在用作阴性对照的非特异性 siRNA 处理的细胞中诱导。除了抗病毒样反应之外，114 个基因是 KD DJ-1 的特异性基因，富集在 RNA 代谢和线粒体功能中。一小部分下调基因（58 个基因）与膜结构、细胞活力和线粒体自噬的失调有关。我们提出，KD DJ-1 的干扰会降低其对氧化应激的保护效力。因此，它通过激活大量基因使细胞不稳定并对 dsRNA 信号产生反应，其中许多基因驱动细胞凋亡、细胞死亡和炎症特征。KD DJ-1 突出了其调节与抗病毒反应、RNA 代谢和线粒体功能相关的基因的能力，显然是通过改变 STAT 活性和下游信号。鉴于 DJ-1 也作为转移性癌症中的致癌基因发挥作用，靶向 DJ-1 可能是一种很有前途的治疗策略，其中操纵 DJ-1 水平可能会降低癌细胞活力并提高癌症治疗的效果。
