Interleukin 7 Up-regulates CD95 Protein on CD4+ T Cells by Affecting mRNA Alternative Splicing PRIMING FOR A SYNERGISTIC EFFECT ON HIV-1 RESERVOIR MAINTENANCE
Interleukin 7 Up-regulates CD95 Protein on CD4+ T Cells by Affecting mRNA Alternative Splicing PRIMING FOR A SYNERGISTIC EFFECT ON HIV-1 RESERVOIR MAINTENANCE
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白介素 7 通过影响 mRNA 选择性剪接上调 CD4( ) T 细胞上的 CD95 蛋白，从而对 HIV-1 储库维持产生协同效应
DOI：
10.1074/jbc.m114.598631
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发表时间：
2015-01-02
影响因子：
4.8
通讯作者：
Zhang, Hui
中科院分区：
文献类型：
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作者：
Yin, Yue;Zhang, Shaoying;Zhang, Hui
背景：IL-7可上调记忆性CD 4（+）T细胞上CD 95的表达，但其机制尚不清楚。结果：IL-7通过上调miR-124的表达，降低剪接调节因子PTB的表达，抑制CD 95 mRNA的剪接。结论：IL-7通过调节CD 95的选择性剪接，促进CD 95的表达。重要性：IL-7和CD 95配体的共刺激作用有利于HIV-1储库的维持，IL-7已被用作HIV-1感染的免疫调节剂和潜伏期逆转剂。虽然IL-7可以恢复HIV-1感染患者的循环CD 4（+）T细胞计数，但IL-7的抗凋亡和增殖作用似乎有利于HIV-1潜伏感染的记忆性CD 4（+）T淋巴细胞的存活和扩增。IL-7已被证明可提高HIV-1感染者CD 4（+）T细胞上的CD 95，并使CD 4（+）T淋巴细胞接受CD 95介导的增殖或凋亡信号。在这里，我们观察到通过增加microRNA-124，IL-7下调剪接调节剂聚嘧啶束结合蛋白（PTB），导致包含跨膜结构域编码的CD 95 mRNA外显子6，随后，记忆CD 4（+）T细胞上的CD 95升高。此外，IL-7上调细胞FLICE样抑制蛋白（c-FLIP）并刺激c-Jun N-末端激酶（JNK）磷酸化，这将记忆CD 4（+）T淋巴细胞中的CD 95信号转导转换为存活模式。因此，通过IL-7/IL-7 R和FasL/CD 95信号通路的共刺激增强了IL-7介导的HIV-1潜伏感染的记忆性CD 4（+）T淋巴细胞的存活和扩增。总的来说，我们已经证明了IL-7介导的HIV-1储库维持的新机制。
Background: IL-7 can up-regulate CD95 expression on memory CD4(+) T cells, but the mechanism remains unclear. Results: IL-7 elevates miR-124 to decrease the expression of splicing regulator PTB and represses CD95 mRNA splicing. Conclusion: IL-7 elevates CD95 expression by regulating its alternative splicing. Significance: Our data demonstrate that the co-stimulation of IL-7 and CD95 ligand benefits HIV-1 reservoir maintenance.Interleukin-7 (IL-7) has been used as an immunoregulatory and latency-reversing agent in human immunodeficiency virus type 1 (HIV-1) infection. Although IL-7 can restore circulating CD4(+) T cell counts in HIV-1-infected patients, the anti-apoptotic and proliferative effects of IL-7 appear to benefit survival and expansion of HIV-1-latently infected memory CD4(+) T lymphocytes. IL-7 has been shown to elevate CD95 on CD4(+) T cells in HIV-1-infected individuals and prime CD4(+) T lymphocytes to CD95-mediated proliferative or apoptotic signals. Here we observed that through increasing microRNA-124, IL-7 down-regulates the splicing regulator polypyrimidine tract binding protein (PTB), leading to inclusion of the transmembrane domain-encoding exon 6 of CD95 mRNA and, subsequently, elevation of CD95 on memory CD4(+) T cells. Moreover, IL-7 up-regulates cellular FLICE-like inhibitory protein (c-FLIP) and stimulates c-Jun N-terminal kinase (JNK) phosphorylation, which switches CD95 signaling to survival mode in memory CD4(+) T lymphocytes. As a result, co-stimulation through IL-7/IL-7R and FasL/CD95 signal pathways augments IL-7-mediated survival and expansion of HIV-1-latently infected memory CD4(+) T lymphocytes. Collectively, we have demonstrated a novel mechanism for IL-7-mediated maintenance of HIV-1 reservoir.