Talaromyces marneffei suppresses macrophage inflammation by regulating host alternative splicing.
Talaromyces marneffei suppresses macrophage inflammation by regulating host alternative splicing.
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DOI：
10.1038/s42003-023-05409-6
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发表时间：
2023-10-16
影响因子：
5.9
通讯作者：
Liang, Hao
中科院分区：
文献类型：
--
作者：
Wei, Wudi;Wang, Gang;Zhang, Hong;Bao, Xiuli;An, Sanqi;Luo, Qiang;He, Jinhao;Chen, Lixiang;Ning, Chuanyi;Lai, Jingzhen;Yuan, Zongxiang;Chen, Rongfeng;Jiang, Junjun;Ye, Li;Liang, Hao
马尔尼菲踝节菌（T. marneffii）免疫逃逸在踝节菌病的发病机制中至关重要。目前已知马尔尼菲毛虫通过多种策略实现免疫逃逸。然而，细胞选择性剪接（AS）在免疫逃逸中的作用仍不清楚。在这里，我们通过高通量 RNA 测序描绘了马尔尼菲毛虫感染后巨噬细胞中的 AS 景观，并检测到 NCOR2 / SMRT 的截短蛋白，命名为 NCOR2-013，该蛋白在马尔尼菲毛虫感染后显着上调。机制分析表明，NCOR2-013 与 TBL1XR1 / TBLR1 和 HDAC3 形成共抑制复合物，从而通过抑制组蛋白乙酰化来抑制 JunB 介导的促炎细胞因子的转录激活。此外，我们将 TUT1 确定为 AS 调节因子，调节 NCOR2-013 的产生并促进马尔尼菲木霉免疫逃避。总的来说，这些发现表明马尔尼菲毛虫通过 TUT1 介导的 NCOR2 / SMRT 选择性剪接逃避巨噬细胞杀伤，从而深入了解马尔尼菲毛虫免疫逃避的分子机制和踝部真菌病治疗的潜在靶点。该研究探讨了马尔尼菲毛虫感染的免疫逃避机制，强调了选择性剪接（AS）的作用。马尔尼菲毛霉触发 NCOR2-013 上调，通过组蛋白乙酰化抑制促炎细胞因子的产生。 TUT1 调节 NCOR2-013，有助于免疫逃避。这揭示了马尔尼菲木霉在分子水平上的免疫逃避，提供了潜在的踝部真菌病治疗靶点。
Talaromyces marneffei (T. marneffei) immune escape is essential in the pathogenesis of talaromycosis. It is currently known that T. marneffei achieves immune escape through various strategies. However, the role of cellular alternative splicing (AS) in immune escape remains unclear. Here, we depict the AS landscape in macrophages upon T. marneffei infection via high-throughput RNA sequencing and detect a truncated protein of NCOR2 / SMRT, named NCOR2-013, which is significantly upregulated after T. marneffei infection. Mechanistic analysis indicates that NCOR2-013 forms a co-repression complex with TBL1XR1 / TBLR1 and HDAC3, thereby inhibiting JunB-mediated transcriptional activation of pro-inflammatory cytokines via the inhibition of histone acetylation. Furthermore, we identify TUT1 as the AS regulator that regulates NCOR2-013 production and promotes T. marneffei immune evasion. Collectively, these findings indicate that T. marneffei escapes macrophage killing through TUT1-mediated alternative splicing of NCOR2 / SMRT, providing insight into the molecular mechanisms of T. marneffei immune evasion and potential targets for talaromycosis therapy. The study explores immune evasion mechanisms of T. marneffei infection, highlighting the role of alternative splicing (AS). T. marneffei triggers the upregulation of NCOR2-013, inhibiting pro-inflammatory cytokine production via histone acetylation. TUT1 regulates NCOR2-013, contributing to immune evasion. This sheds light on T. marneffei’s immune evasion at the molecular level, offering potential talaromycosis therapy targets.
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影响因子：
64.8
作者：
Kim, Min-Sik;Pinto, Sneha M.;Getnet, Derese;Nirujogi, Raja Sekhar;Manda, Srikanth S.;Chaerkady, Raghothama;Madugundu, Anil K.;Kelkar, Dhanashree S.;Isserlin, Ruth;Jain, Shobhit;Thomas, Joji K.;Muthusamy, Babylakshmi;Leal-Rojas, Pamela;Kumar, Praveen;Sahasrabuddhe, Nandini A.;Balakrishnan, Lavanya;Advani, Jayshree;George, Bijesh;Renuse, Santosh;Selvan, Lakshmi Dhevi N.;Patil, Arun H.;Nanjappa, Vishalakshi;Radhakrishnan, Aneesha;Prasad, Samarjeet;Subbannayya, Tejaswini;Raju, Rajesh;Kumar, Manish;Sreenivasamurthy, Sreelakshmi K.;Marimuthu, Arivusudar;Sathe, Gajanan J.;Chavan, Sandip;Datta, Keshava K.;Subbannayya, Yashwanth;Sahu, Apeksha;Yelamanchi, Soujanya D.;Jayaram, Savita;Rajagopalan, Pavithra;Sharma, Jyoti;Murthy, Krishna R.;Syed, Nazia;Goel, Renu;Khan, Aafaque A.;Ahmad, Sartaj;Dey, Gourav;Mudgal, Keshav;Chatterjee, Aditi;Huang, Tai-Chung;Zhong, Jun;Wu, Xinyan;Shaw, Patrick G.;Freed, Donald;Zahari, Muhammad S.;Mukherjee, Kanchan K.;Shankar, Subramanian;Mahadevan, Anita;Lam, Henry;Mitchell, Christopher J.;Shankar, Susarla Krishna;Satishchandra, Parthasarathy;Schroeder, John T.;Sirdeshmukh, Ravi;Maitra, Anirban;Leach, Steven D.;Drake, Charles G.;Halushka, Marc K.;Prasad, T. S. Keshava;Hruban, Ralph H.;Kerr, Candace L.;Bader, Gary D.;Iacobuzio-Donahue, Christine A.;Gowda, Harsha;Pandey, Akhilesh
通讯作者：
Pandey, Akhilesh
影响因子：
5.3
作者：
Guenther, MG;Barak, O;Lazar, MA
通讯作者：
Lazar, MA
影响因子：
7.3
作者：
Ghiboub M;Zhao J;Li Yim AYF;Schilderink R;Verseijden C;van Hamersveld PHP;Duarte JM;Hakvoort TBM;Admiraal I;Harker NR;Tough DF;Henneman P;de Winther MPJ;de Jonge WJ
通讯作者：
de Jonge WJ
影响因子：
3.7
作者：
Rodrigues R;Grosso AR;Moita L
通讯作者：
Moita L
影响因子：
--
作者：
Andrianopoulos, Alex
通讯作者：
Andrianopoulos, Alex