作为具有ATP依赖性RNA解绕酶的DEAD-box家族的新型人类成员，DDX20在哺乳动物细胞的分子水平上可检测到，针对DDX20的单克隆抗体已升高至103 kDa[6]。随后的研究表明，编码DDX46蛋白的隐杆菌基因Mel-20在其整个发育过程中表达，并在发育过程中发挥促进作用[7]。细胞水平的监测结果显示，在肝细胞癌组织中可检测到DDX20表达降低，从而影响疾病进程[8,9]。此外，在组织和器官水平上，DDX20在睾丸中表达，甚至在产生类固醇和非类固醇的组织中表达[10]。此外，DDX20在某些癌组织中显著过表达，例如肝细胞癌和结直肠癌、前列腺癌和胃癌，通常表明预后良好[11,12,13,14]。DDX20首先由单性生殖多细胞生物Dictyostelium discoideum的基因组编码，并保留在出生后动物中[15]。一些药物，如他汀类药物，也可以通过甲羟戊酸途径和RhoA下游抑制DDX20的表达[16]。

DEAD-box RNA消解酶家族具有独特的Asp-Glu-Ala-Asp（D-E-A-D）序列基序[17]。所有DEAD-box开盖酶（包括DDX20）在N端都有一个保守的核心结构域，主要包括两个重组酶A（RecA）样结构域[18]。如图1所示，该核心结构域包括1个保守基序，即Q、I、Ia、Ib、II、III、IV、V和VI，它们参与ATP结合和水解、RNA底物结合、通过ATP结合水解调节开盖酶活性以及调节ATP酶活性[19]。D-E-A-D 序列基序主要存在于高度保守的基序 II 中，这也是“DEAD-box”名称的来源。非保守的N端和C端辅助结构域位于核心结构域的两侧，大小从几个到几百个氨基酸不等。这些主要与开胃酶的特定功能有关[20]。例如，DDX20的C端区域是维持其解偶联解旋酶活性所必需的[<>]。

DDX20参与有关其亚细胞定位的复杂生物学过程。作为SMN复合体的成员，DDX20在snRNP的组装中发挥作用[21]。snRNP的组装过程涉及从细胞质到细胞核的定位过渡，并且DDX20相应地在此过程中经历了位置的变化[22]。在进行snRNP组装过程之前，DDX20最初与细胞质中的其他蛋白质共组装以形成完整的SMN复合物。SMN复合物广泛存在于细胞质中，不包括肌肉细胞。随后，DDX20将SmB、SmD2和SmD3共组装到细胞质中的snRNA特异性位点[23]。

在5'端组装和封顶后，snRNP在SMN复合物和导入因子导入β的帮助下进入细胞核，DDX20与snRNP相关[24,25]。在细胞核中，SMN复合物与snRNP共同靶向称为Cajal小体（CBs）的亚核细胞器，但此后不久与snRNP分离[26,27]。

DDX20在细胞质和细胞核中的定位受到几个影响因素的影响。首先，SMN复合物经历广泛的磷酸化修饰，SMN复合物中几种蛋白质（包括DDX20）的去磷酸化修饰阻碍了SMN复合物进入细胞核的运动及其在CB中的积累[28]。其次，在正常条件下，SMN复合物从细胞质到细胞核的转变需要完整的sumo-SUMO的偶联受损类似于磷酸化修饰，可以减少SMN复合物的核定位，导致其异常的细胞质积累[29]。有趣的是，SMN蛋白可以作为乙酰转移酶CBP的特异性靶标，并且已经鉴定出乙酰化位点K119。然而，与前两次修饰不同，乙酰化促进SMN向细胞核移动并增强其细胞质定位[30]。最后，SMN复合体成员Gemin4包含三个假定的核定位信号（NLS）基序，这些基序推动SMN复合物中其他Gemin蛋白从细胞质进入细胞核，以剂量依赖性方式破坏Cajal-body标记的蛋白质线圈的亚核定位[31]。因此，在细胞质中高度定位的DDX20在起作用时与SMN复合物一起进入细胞核，这一过程可能受到一系列因素的影响。

现有研究表明，运动神经元蛋白SMN与Gemin2-8蛋白（包括DDX20/Gemin3和Unrip）一起形成稳定的SMN复合物，其中DDX20/Gemin3在该复合物的组装中起着至关重要的作用[32,33,34]。SMN复合物的组装过程是模块化的，涉及几种SMN复合物蛋白质的物理结合。SMN/Gemin8/Gemin7位于复合物的核心，募集其他蛋白质形成完整的组装体[34]。

作为分子伴侣，SMN复合物促进剪接体小核糖核蛋白（snRNP）的组装和功能[35]。snRNP由富含U的小核RNA（snRNA）和7个小（Sm）或Sm样（LSm）蛋白组成，组装成细胞质中完整的茎环结构[34,36]。这种装配过程涉及多个SMN复杂组件，需要蜂窝位置偏移。

最初，snRNA（不包括U6）在细胞核中被RNA聚合酶II转录为前体RNA，在3'端包含一个额外的茎环结构，在7'端包含一个单甲基化的m7GpppG（m5G）帽结构[37]。该前体snRNA随后通过其5′帽结构与包含多种蛋白质的snRNA输出复合物结合，导致其输出到细胞质中[38]。

在细胞质中，Sm和Sm样蛋白首先与氯化物电导调节蛋白（pICln）和蛋白精氨酸甲基转移酶5（PRMT5）复合物结合。然后将这些蛋白质预先排列到空间位置，并在加入SMN复合物后分离，SMN复合物将Sm和Sm样蛋白组装成snRNA上的蛋白质结合位点，形成具有七元环结构的完整snRNP[39,40]。

最后，具有Sm核心的snRNA在其5′末端经历甲基化，由三甲基鸟苷合酶1（TGS1）催化，形成m3G帽结构。该过程由SMN复合物和导入蛋白β介导，促进细胞核中剪接功能的表现[15,41]。这种组装过程很复杂，涉及不同的组件扮演独特的角色。本节的重点是简要概述DDX20 / Gemin3在此过程中的作用。

首先，SMN复合物在snRNP组装中起着至关重要的不可替代的作用，而DDX20 / Gemin3对于复合物的稳定是必不可少的。在SMN复合物中，DDX20 / Gemin3与SMN蛋白以及Gemin2,4和5结合。这种相互作用招募Gemin3作为SMN复合体的核心成分，促进其稳定性[42,43,44]。SMN复合物的核心组分（包括Gemin3）的sumo-Gemin3的脱硫修饰可能会减少与几种核心蛋白的结合，并可能影响细胞定位SMN复合物[29]。如图2所示，Gemin3与其他几种蛋白质形成SMN复合物，并且各种蛋白质之间存在相互作用。

SMN复合物的组成蛋白相互作用;因此，一种蛋白质的变化会影响其他蛋白质的稳定性和丰度。例如，SMN蛋白的减少导致宝石消失和几种宝石蛋白水平降低，最终影响snRNP组装[45]，从而表明DDX20/Gemin3在维持SMN复合物稳定性方面的潜在作用。

其次，SMN复合物受到磷酸化的广泛调控。DDX20/Gemin3含有13个磷酸化位点，是复合物中磷酸化程度最高的蛋白质之一。DDX20/Gemin3和其他复合蛋白的磷酸化影响细胞质和细胞核之间SMN复合物的交换以及snRNP的组装[28]。DDX20 / Gemin3在SMN复合物中的作用延伸到生物系统。它在果蝇中胚层和肌肉层中的缺失可导致运动障碍、严重的发育缺陷，甚至幼虫死亡，并且可能与SMN蛋白突变引起的SMA有关[46]。

现有研究报告称，Gemin3显着影响snRNP组装。值得注意的是，通过RNAi敲低Gemin3后snRNP组装的破坏提供了最直接的证据[47,48]。vSMN复合物可以与Sm蛋白结合，并通过与snRNA结合促进其组装成完整的snRNP。Gemin3可以与Sm蛋白中的SmB、SmD2和SmD3相互作用，这一事实表明其在snRNP生物发生中的作用[23]。

Almstead等人提供了关于Gemin3在snRNP组装中的作用的进一步证据，他们发现脊髓灰质炎病毒编码的蛋白酶3Apro的Gemin2特异性切割导致Gemin3蛋白水平降低，这导致Sm蛋白从细胞核到细胞质的特异性重排和snRNP组装的减少[47].此外，Gemin3在遗传和物理上与snRNP组装中的两个因子相互作用，即pI-Cln和Tgs1。 删除pICln和Tgs1将导致与Gemin3缺乏症相同的活力和运动表型[49]。编码蛋白质TDP-43和FUS的两个肌萎缩侧索硬化症（ALS）基因的破坏会加剧表型缺陷。这些结果为DDX20在snRNP组装和运动神经元疾病中的作用提供了额外的证据[50]。图3显示了SMN复合物的组装以及易位过程。

近年来，DDX20在转录中的作用被报道得越来越多，并且已经报道了大量关于其作为转录调节剂作用的证据。DDX20主要通过与核受体类固醇生成因子-1（SF-1）相互作用来抑制转录[51]。SF-1是转录因子核受体超家族的成员，是下丘脑-垂体-性腺轴和肾上腺皮质内分泌因子的关键调节因子[52]。DDX20在产生类固醇的组织中高表达，类固醇组织也高表达SF-1[10]。DDX20通过其非保守的C端结构域直接与SF-1的C端抑制结构域相互作用，抑制SF-1的转录活性[20]。进一步的研究已经详细阐述了DDX20与SF-1相互作用并抑制其转录活性的具体机制。转录因子SF-1的转录活性受其他转录因子、共调控因子和翻译后修饰的影响[53]。Sumoylization是SF-1翻译后发生的泛素样修饰，可抑制SF-1激活靶基因表达的能力[54]。DDX20在与SF-1蛋白直接相互作用以抑制其转录活性后，增强由活化的STATs蛋白抑制剂（一种E3-SUMO连接酶）介导的SF-1的苏莫化[55]。这种相互作用也有助于SF-1重新定位到离散的核小体或病变。探索这种抑制机制表明，组蛋白去乙酰化酶参与转录因子SF-1的sumo-ization修饰，并且与核心加压因子的相互作用较少;然而，它可能在苏莫酰化过程中作为E3连接酶起作用[56]。

SF-1在节肢动物中具有同源基因，称为FTZ-F1（fushi tarazu因子-1）[57]。一项研究证实，DDX20通过酵母双杂交测定法与副苜蓿中的FTZ-F1相互作用，并报道DDX20可以通过类似于RNAi抑制SF-1的机制抑制FTZ-F1表达[58]。FTZ-F1与卵黄原素（VTG）密切相关，参与卵巢中卵黄素的发育，可影响几种内分泌激素的分泌[59]。通过DDX1抑制FTZ-F20最终会影响卵巢发育。

叉头转录因子（FOXL）2是与FTZ-F1和DDX20密切相关的转录因子，在调节卵巢发育方面也起着重要作用。在卵巢中，FOXL2参与调节胆固醇和类固醇代谢、细胞凋亡、活性氧解毒和细胞增殖[60]。最初，发现DDX20与FOXL2相互作用，它们在细胞中的共表达增强了FOXL2介导的卵巢细胞死亡[61]。随后的研究证实，FOXL2与DDX20和FTZ-F1相互作用，不仅通过DDX20调节滤泡细胞凋亡来下调VTG合成，而且还可能通过FTZ-F1调节类固醇生成途径。

除F-1外，已发现DDX20与另外两种转录因子相互作用，与SF-1相比，通过不同的机制抑制其活性。首先，DDX20可以通过其C端结构域与有丝分裂的Ets转录抑制剂（PE-1 / METS）结合。Ets是一种转录因子，可作为核靶点激活Ras-MAPK信号通路，而Ets家族的另一个成员PE-1/METS则作为Ets抑制剂抑制Ras依赖性Ets靶基因增殖，从而导致巨噬细胞生长停滞[62]。

DDX20通过其C端结构域与PE-1/METS的N端结构域相互作用，具有抑制作用。在此过程中，DDX20还募集组蛋白去乙酰化酶HDAC-2和HDAC5等因子[63]。然而，有趣的是，这种由DDX20介导的转录抑制仅针对单个启动子，例如c-myc和cdc2，而不影响Ets三元复合物促进的转录[64]。

Thus, DDX20 does not undergo sumoacylation as DDX5 and its transcription regulation activity do not solely rely on a single intrinsic function but involve multiple mechanisms, many of which depend on its unique noncore C-terminal domain. This multifaceted approach to transcriptional regulation reinforces the complexity of the function of DDX20 in this essential cellular process.

DDX20/Gemin3 also contributes to the maturation of miRNA. The biogenesis of miRNA begins with the transcription of miRNA genes into primary miRNA (pri-miRNA) by RNA polymerase II. The pri-miRNA is subsequently processed into a precursor miRNA (pre-miRNA) of ~70 nucleotides by a complex containing the RNase III endonuclease Drosha and a protein containing a double-stranded RNA-binding structural domain (dsRBD) named Pasha (DGCR8) [77,78].

Subsequently, the stem–loop-structured pre-miRNAs are transported into the cytoplasm, which is dependent on the GTP-dependent transport protein Exportin-5 (Exp5) [79]. In the cytoplasm, the RNase III endonuclease Dicer processes pre-miRNA into an siRNA–miRNA duplex of ~22 nucleotides. The mature miRNA strand is subsequently retained in the RNA-induced silencing complex (RISC) along with other proteins [80].

Although most Gemin3 and Gemin4 are components of the SMN complex, the complexes of Gemin3 and Gemin4 isolated from HeLa and neuronal cells are not part of the SMN complex. Instead, these complexes coprecipitate with polyribosomes [71,81,82]. Numerous studies have established the connection of Gemin3/DP103 and Gemin4 with the Argonaute (Ago) protein family member Argonaute [60,83,84]. Figure 4 shows the mIRNAde1 maturation process and the role Gemin3 plays in it.

MiRNAs can inhibit the translation of partially complementary target messenger RNAs by directing the sequence-specific degradation of both fully and partially complementary target mRNAs [85,86]. However, regarding the specific role of Gemin3 in miRNA biogenesis, researchers suggest that Gemin3 is a member of RISC, given the presence of the Gemin3 protein in the peripheral axons of the mouse sciatic nerve and its capacity to form a multiprotein RISC in response to specific treatment [72].

RISC was not previously identified as having decapping components for siRNAs and miRNAs within the complex. Consequently, researchers posit that Gemin3 serves as a decapping enzyme within the RISC complex and plays a role in RNA decapping or recombination during miRNA maturation as well as in target RNA recognition [72].

The NF-κB family comprises six distinct components. When activated, they produce various proinflammatory factors that regulate inflammation and significantly contribute to innate immunity [87,88]. The NF-κB signaling pathway controls the expression of proinflammatory cytokines and anti-infective factors, including TNF-α, interleukin-1 (IL-1), IL-6, IL-8, adhesion molecules, and cc chemokine ligand 5 (CCL5) [89]. In addition, NF-κB signaling pathway governs cellular processes such as cell proliferation, differentiation, and apoptosis [90,91].

While the NF-κB signaling pathway has an antiapoptotic role, its dysregulation has been implicated in the pathogenesis of most human malignancies [92]. Therefore, manipulating the NF-κB signaling pathway can provide a path for developing novel methods to combat diseases such as cancer [93]. For instance, alterations in DDX20 expression in cancer tissues can affect NF-κB activity, leading to cancer development [94].

DDX20 can have two distinct effects on the NF-κB signaling pathway. Numerous studies have reported that DDX20 does not directly affect NF-κB activity but rather acts through a naturally occurring small non-coding RNA (miRNA) intermediate. The present study demonstrated that DDX20 can modulate the signaling of the NF-κB pathway through miRNA-22, miRNA-140-3p, and miR-222 [8,95]. Additionally, miR-361-5p was found to regulate DDX20, thereby influencing NF-κB pathway signaling [13]. First, DDX20 can inhibit NF-κB activity. DDX20 and miRNAs together form a ribonucleoprotein complex, and miRNA library screening has revealed that several miRNAs can inhibit NF-κB activation. This inhibition prevents the activation of the NF-κB signaling pathway [8]. It has been well established that miRNAs can inhibit NF-κB activity by regulating the expression of two NF-κB coactivators, namely nuclear receptor coactivator protein 1 (NCOA1) and nuclear receptor-interacting protein 1 (NRIP1) [96]. Conversely, DDX20 can also enhance NF-κB activity, notably by impairing miRNA function by decreasing its own expression, leading to impaired NF-κB inhibitory miRNA function [8,97].

Another way DDX20 can inhibit the NF-κB signaling pathway is through miRNA-140 dysfunction, which increases expression of its downstream target gene Dnmt1 and the methylation of CpG islands in the promoter region of metallothionein (MTs) and decreases MT expression, leading to enhanced NF-κB activity [9]. Second, DDX20 can boost the NF-κB signaling pathway by enhancing the phosphorylation of TAK 1, where it acts as a cofactor of TAK1, thus enhancing the activity of the NF-κB signaling pathway [98]. More details regarding this aspect will be discussed in the subsequent sections.

The TP53 gene encodes the key p53 transcription factor and evolutionarily conserved tumor suppressor involved in maintaining genomic stability [99]. To accomplish this, it activates DNA repair responses and initiates apoptosis in damaged host cells [100]. Its activation controls core programs such as cell cycle arrest and apoptosis [101]. In addition, p53 is closely related to immune responses as well as various inflammatory diseases [102].

In fact, the effect of DDX20 on the p53 signaling pathway can be realized by directly affecting the pivotal p53 protein. Changes in DDX20 expression can consequently impact the organism’s state through the p53 signaling pathway. Reportedly, DDX20 interacts with p53 protein through its C-terminal structural domain [1]. The normal expression of DDX20 stabilizes motor neurons and uses genomic stability and regulates Mdm2 splicing to restrain the p53 signaling pathway, thereby preserving normal neural development [4].

In this context, several cytokines, such as oligodendrocyte transcription factor 2 (Olig2) and Epstein–Barr (EB) nuclear antigen 3C (EBNA3C), can directly interact with DDX20 to stabilize its expression. This interaction inhibits transcription and apoptosis caused by the p53 signaling pathway and its downstream genes within the organism [4,67].

DDX20 not only plays a role in the invasion of multiple pathogens but also plays an active role in the case of multiple tumorigenesis.

In breast cancer, DDX20 is involved in cell signaling pathway activity, which is a key factor in tumorigenesis. The NF-κB signaling pathway is more closely linked to tumor development, and, reportedly, it can improve cancer cell survival, promote cancer cell angiogenesis and migration, and has other characteristics alongside being associated with the poor prognosis of cancer diseases [106]. It is because of the role of the NF-κB signaling pathway in tumor growth that it can be used to inhibit carcinogenesis [107]. DDX20 is an important cofactor for the phosphorylation of transforming growth factor-β-activated kinase-1 (TAK1) by NF-κB-activated IκB kinase 2 (IKK2), enhancing the activity of the NF-κB signaling pathway by stimulating TAK1 phosphorylation [108]. TAK1 is a member of the mitogen-activated protein kinase (MAPK) family that plays a key regulatory role as an upstream component of the NF-κB signaling pathway [109]. Enhanced NF-κB signaling pathway activation increases in the expression of two downstream products, matrix metalloproteinase 9 (MMP9) and multidrug resistance gene 1 (MDR1), and, as the chief role of MMP9 is to degrade the extracellular matrix, this change further increases tumor metastasis and drug resistance [19,110]. Conversely, enhanced NF-κB activity and increased downstream MMP9 expression would also lead to increased DDX20 expression. Thus, the establishment of the DDX20–NF-κB–MMP9 axis could better reveal the mechanism by which DDX20 can promote cancer development [69]. In addition, DDX20 may exhibit an miRNA-processing role in breast cancer. A group of studies reported that DDX20 exhibited a negative correlation with an miRNA, namely miR-222, suggesting that DDX20 affects the NF-κB activity through miR-222 to promote breast cancer development [95]. Based on this property of DDX20 in breast cancer, researchers believe that DDX20 can serve as an active alternative to certain anticancer drugs. DDX20 enhances the sumolylation modification of YAP, thereby increasing YP-TEAD dependence and statin sensitivity in patients with triple-negative breast cancer [16]. Statins, such as simvastatin (SMV), are cholesterol-reducing lipophilic statins that inhibit DDX20 expression by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), which is positively associated with DDX20 [103]. Figure 5A demonstrates that DDX20 affects tumorigenesis and development through the NF-κB signaling pathway. Further studies have reported that simvastatin downregulates DDX20 not only through the classical mevaleric acid pathway and the downstream component of RHoA but also through the miRNA-mediated nonclassical pathway [111,112]. Simvastatin ultimately inhibits breast cancer by decreasing DDX20 expression. In addition to its role through the NF-κB signaling pathway and miR-222, DDX20 acts through the cellular redox pathway and Wingless/Integrated(Wnt) signaling pathway. In cancer stem cells (CSCS), DDX20 drives a positive feedback loop wherein DDX20 promotes its transcriptional regulation via transcription factor 4 (TCF 4) to stimulates the aggressiveness of breast cancer via Wnt/beta-catenin signaling [113]. Another example of the carcinogenic effect of DDX20 is in prostate cancer. High DDX20 expression in the tumor tissue of patients with prostate cancer also enhances tumor growth and metastasis via the DDX20–NF-κB–MMP9 axis [11]. These results suggest a role of DDX20 in tumor metastasis.

In contrast to its role in prostate and breast cancers, DDX20 acts as a tumor suppressor in liver cancer and suppresses tumorigenesis. As reported, tumor genomics of RNAi performed in a mouse model of hepatocellular carcinoma has identified DDX20 as a tumor suppressor [104]. MiRNAs can regulate the expression of target genes, and, while they reportedly function as suppressors or oncogenes in several tumors, their expression tends to be low in tumor tissue [105,114,115]. As mentioned above, miRNA-140-3p and miRNA-22, as miRNA, can inhibit NF-κ B activity, and DDX20 deletion in hepatocellular carcinoma (HCC) impaired this inhibitory effect of miRNA-140-3p and miRNA-22 [116]. Decreases in miRNA-140-3p and miRNA-22 expression affected the inhibitory effect of NCOA1 and NRIP1 on NF-κB activity. In addition, maintaining NF-κB activity led to inflammation, further exacerbating hepatocellular carcinoma [96]. In addition, miR-140-3p dysfunction promotes tumorigenesis by increasing the expression of its downstream target gene Dnmt1 and the methylation of CpG islands in the promoter region of metallothionein (MTs) and decreasing MT expression, consequently enhancing NF-κB signaling pathway activity [9]. Therefore, it is inferred that DDX20 can function as a tumor suppressor. Certain proteins, such as death-associated protein kinase 1 (DAPK), can inhibit the proteasomal degradation of DDX20, maintaining high DDX20 levels [98]. Elevated DDX20 levels inhibit hepatocellular carcinoma cell migration and invasion by regulating the NF-κB signaling pathway. Figure 5B demonstrates that DDX20 affects tumorigenesis and development through the NF-κB signaling pathway as a tumor suppressor.

Thus, DDX20 acts either as an oncogenic factor promoting tumor development or as a tumor suppressor inhibiting tumor progression. In conclusion, DDX20 plays a role in the regulation of hepatocellular carcinoma development through various miRNAs, including miRNA-140-3P and miRNA-22, as well as in breast cancer development through miRNA-222. DDX20 primarily functions by influencing the NF-κB signaling pathway. Beyond its roles in breast cancer, prostate cancer, and hepatocellular carcinoma, DDX20 has been implicated in several other tumors [117].

Early research identified the capacity of DDX20 to interact with two vitally encoded nuclear antigens of the EB virus (EBV), EBNA2 and EBNA3C, and modulate the transcription of viral and cellular genes [68]. EBV is a lymphocryptovirus (LCV) herpesvirus that predominantly infects B lymphocytes and is noted for its ability to maintain long-term latent infections in the body while expressing a limited number of “latent” genes [119,120].

According to the report, EBNA2 can serve as a transcriptional activator of transformative viral and cellular genes by regulating two EBNA2-regulated viral promoters (TP1 and LMP/TP2 promoter) following its binding to the homologous promoter element RBPJkappa [121,122]. This promoter activation by EBNA2 is facilitated by cellular enhancer binding proteins and EBV nucleoproteins [123,124].

Later studies revealed that DDX20 can bind EBNA2 and survival motor neuron (SMN) proteins via its C-terminal structural domain, reporting that EBNA2 targets the spliceosome complex to release the SMN protein after binding DDX20, which ultimately acts as a coactivator in RNA polymerase II transcriptional complexes on the LMP1 promoter [125]. An additional finding suggests that, although RBPJkappa is necessary for EBNA2 transactivation, it is insufficient and it needs to be achieved through the EBNA2 and SMN proteins, underscoring the crucial role of DDX20 [125].

Conversely, EB nuclear antigen 3C (EBNA3C) is an important latent antigen that induces B lymphocyte immortalization in EBV through its contribution to viral pathogenicity. This is achieved via the putative bZIP structural domain at the N terminus of the protein and its interaction with cellular transcription factors RBPJkappa and HDAC1 to regulate transcriptional activation [126,127]. Additionally, EBNA3C facilitates the transcriptional reprogramming of various host cell genes, which is associated with the lengthy latency of EBV [128].

Similarly, DDX20 interacts with EBNA3C via its C-terminal structural domain. DDX20 can be stabilized by EBNA3C to form a complex with p53, which subsequently blocks p53-mediated transcriptional activity and apoptosis [67]. Moreover, based on related studies, EBNA2 and EBNA3C can reportedly disrupt the interaction between DDX20 and the transcription factor METS, thereby activating cellular proto-oncogenes [129]. This connection between DDX20 and EBV led to the initial discovery of a link between DDX20 and cancer.

In addition to EBV, DDX20 has significant connections with other viruses. DDX20 expression has previously been identified to vary in tumor tissues. In terms of changes in its expression upon viral infection, researchers reported that DDX20 is differentially expressed at distinct stages of human immunodeficiency virus type 1 (HIV-1) infection and found that DDX20 interacts with the HIV-1 coprotein Vpr as early as 2012 [76].

Further analysis of global miRNA and mRNA expression through microarray and quantitative reverse transcription polymerase chain reaction in well-characterized HIV-1 latently and actively infected cells revealed that DDX20 was significantly upregulated in the former [130]. Conversely, a downregulation of DDX20 expression was detected during HIV-1 replication. DDX20 was directly degraded by the vRNA translation product of HIV-1, the Vpr protein, via the DCAF1/DDB1/CUL4 E3 ubiquitin ligase-mediated degradation pathway [131]. Owing to these alterations in DDX20 expression, it is thought to play a part in HIV-1 replication. However, the precise mechanism underlying the potential inhibitory effect of DDX20 remains unclear, thus necessitating further research.

DDX20 can enhance Interferon regulatory factor 3 (IRF3) phosphorylation levels by promoting the interaction between TBK1 and IRF3, which further promotes IFN-β expression, ultimately inhibiting the replication of VSV and HSV-1 through INF-stimulated genes (ISG) [2]. This opens up avenues for investigating the role of DDX20 in innate immunity research. Thus, although the role of DDX20 in suppressing viral infection and innate immunity has not been extensively studied, it has great research potential.