ZAP isoforms regulate unfolded protein response and epithelial- mesenchymal transition.
ZAP isoforms regulate unfolded protein response and epithelial- mesenchymal transition.
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ZAP亚型调节未折叠蛋白反应和上皮-间质转化。
DOI：
10.1073/pnas.2121453119
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发表时间：
2022-08-02
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
人锌指抗病毒蛋白ZAP能有效地抑制SARS-CoV-2和HIV等多种重要病毒。ZAP有两种风格，一种是长的，另一种是短的，它们的功能略有不同，需要定性。我们仔细剖析了这些ZAP变体是如何产生的，并揭示了ZAP变体调控着许多基因的RNA，这些基因参与了新的细胞途径，包括细胞应激反应和诱导细胞迁移的途径。因此，ZAP作为与癌症相关的重要细胞过程的调节因子而出现。我们对其变体的合成、细胞靶点和途径的阐明对于免疫调节或癌症治疗的药理靶点ZAP至关重要，我们也为其提供了概念上的证据。人类ZAP通过与病毒RNA结合来促进病毒的降解和/或翻译抑制，从而抑制许多病毒，包括艾滋病毒和冠状病毒。然而，ZAP在宿主mRNAs中的调节作用在很大程度上是未知的。两种主要的选择性剪接的ZAP亚型，结构性表达的ZAPL和感染诱导的ZAP，发挥着重叠但不同的抗病毒作用和其他需要进一步鉴定的作用。我们发现剪接因子hnRNPA1/A2、PtBP1/2和U1-SnRNP抑制ZAPS的产生，并证明了在人类细胞中通过剪接开关反义寡核苷酸调节ZAPL/S平衡的可行性。对ZAP-异构体特异敲除细胞的转录分析显示，ZAPL/S靶向的宿主mRNAs具有广泛的细胞功能，如未折叠蛋白反应、上皮-间充质转化和先天免疫。我们建立了内源ZAPL和ZAPS分别定位于膜室和胞浆，并且差异定位与它们的靶RNA特异性相关。我们发现，ZAP亚型在静息和应激条件下调节不同的UPR分支，并在内质网应激过程中影响细胞的存活。我们还为ZAP异构体在EMT相关细胞迁移中的不同功能提供了证据，其影响取决于细胞类型。总之，本研究证明剪接和IPA之间的竞争是ZAPL/S平衡调节的潜在靶点，并报道了受ZAP亚型调控的新的细胞转录本和过程。
The human zinc finger antiviral protein ZAP potently restricts many important viruses such as SARS-CoV-2 and HIV. ZAP comes in two flavors, with a long and a short variant exhibiting slightly different functions that demand characterization. We carefully dissected how these ZAP variants are made, and revealed that the ZAP variants regulate the RNAs of many genes involved in new cellular pathways, including a cellular stress response and a pathway that induces cell migration. Hence, ZAP emerges as a regulator of important cellular processes with relevance to cancer. Our elucidation of the synthesis, cellular targets and pathways of its variants is paramount to pharmacologically target ZAP for immunomodulation or cancer treatment, of which we also provide proof of concept. Human ZAP inhibits many viruses, including HIV and coronaviruses, by binding to viral RNAs to promote their degradation and/or translation suppression. However, the regulatory role of ZAP in host mRNAs is largely unknown. Two major alternatively spliced ZAP isoforms, the constitutively expressed ZAPL and the infection-inducible ZAPS, play overlapping yet different antiviral and other roles that need further characterization. We found that the splicing factors hnRNPA1/A2, PTBP1/2, and U1-snRNP inhibit ZAPS production and demonstrated the feasibility to modulate the ZAPL/S balance by splice-switching antisense oligonucleotides in human cells. Transcriptomic analysis of ZAP-isoform–specific knockout cells revealed uncharacterized host mRNAs targeted by ZAPL/S with broad cellular functions such as unfolded protein response (UPR), epithelial-mesenchymal transition (EMT), and innate immunity. We established that endogenous ZAPL and ZAPS localize to membrane compartments and cytosol, respectively, and that the differential localization correlates with their target-RNA specificity. We showed that the ZAP isoforms regulated different UPR branches under resting and stress conditions and affected cell viability during ER stress. We also provided evidence for a different function of the ZAP isoforms in EMT-related cell migration, with effects that are cell-type dependent. Overall, this study demonstrates that the competition between splicing and IPA is a potential target for the modulation of the ZAPL/S balance, and reports new cellular transcripts and processes regulated by the ZAP isoforms.
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影响因子：
11.8
作者：
Dermit M;Dodel M;Lee FCY;Azman MS;Schwenzer H;Jones JL;Blagden SP;Ule J;Mardakheh FK
通讯作者：
Mardakheh FK
影响因子：
3.5
作者：
Ly, Phuong Thao;Tang, Sze Jing;Roca, Xavier
通讯作者：
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影响因子：
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EMT亚型影响上皮可塑性和细胞迁移模式。
影响因子：
11.8
作者：
Aiello NM;Maddipati R;Norgard RJ;Balli D;Li J;Yuan S;Yamazoe T;Black T;Sahmoud A;Furth EE;Bar-Sagi D;Stanger BZ
通讯作者：
Stanger BZ
锌指抗病毒蛋白低表达与肝细胞癌患者进展和不良生存的关系
影响因子：
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作者：
Liu, Ying;Hu, Cheng;Peng, Liang
通讯作者：
Peng, Liang