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E3 连接酶 VHL 通过抑制糖酵解和诱导白细胞介素-33 受体促进 2 型固有淋巴细胞的成熟和功能。

E3 Ligase VHL Promotes Group 2 Innate Lymphoid Cell Maturation and Function via Glycolysis Inhibition and Induction of Interleukin-33 Receptor.

机构信息

Institute for Immunology, Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100080, China.

La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.

出版信息

Immunity. 2018 Feb 20;48(2):258-270.e5. doi: 10.1016/j.immuni.2017.12.013. Epub 2018 Feb 13.

DOI:10.1016/j.immuni.2017.12.013
PMID:29452935
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5828523/
Abstract

Group 2 innate lymphoid cells (ILC2s) are a specialized subset of lymphoid effector cells that are critically involved in allergic responses; however, the mechanisms of their regulation remain unclear. We report that conditional deletion of the E3 ubiquitin ligase VHL in innate lymphoid progenitors minimally affected early-stage bone marrow ILC2s but caused a selective and intrinsic decrease in mature ILC2 numbers in peripheral non-lymphoid tissues, resulting in reduced type 2 immune responses. VHL deficiency caused the accumulation of hypoxia-inducible factor 1α (HIF1α) and attenuated interleukin-33 (IL-33) receptor ST2 expression, which was rectified by HIF1α ablation or inhibition. HIF1α-driven expression of the glycolytic enzyme pyruvate kinase M2 downmodulated ST2 expression via epigenetic modification and inhibited IL-33-induced ILC2 development. Our study indicates that the VHL-HIF-glycolysis axis is essential for the late-stage maturation and function of ILC2s via targeting IL-33-ST2 pathway.

摘要

2 型固有淋巴细胞 (ILC2s) 是淋巴效应细胞的一个特殊亚群，它们在过敏反应中起着至关重要的作用；然而，它们的调节机制仍不清楚。我们报告称，条件性缺失固有淋巴祖细胞中的 E3 泛素连接酶 VHL 对早期骨髓 ILC2s 的影响很小，但导致成熟 ILC2s 在周围非淋巴组织中的选择性和内在数量减少，从而导致 2 型免疫反应减少。VHL 缺陷导致缺氧诱导因子 1α (HIF1α) 的积累和白细胞介素 33 (IL-33) 受体 ST2 表达的减弱，这可通过 HIF1α 消融或抑制来纠正。HIF1α 驱动的糖酵解酶丙酮酸激酶 M2 的表达通过表观遗传修饰下调 ST2 表达，并抑制 IL-33 诱导的 ILC2 发育。我们的研究表明，VHL-HIF-糖酵解轴通过靶向 IL-33-ST2 通路对 ILC2s 的晚期成熟和功能至关重要。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/990691c9aeb0/nihms942875f7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/88ae105e6c2c/nihms942875f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/b24431208a23/nihms942875f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/7fc457374e1a/nihms942875f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/17acfb603bf5/nihms942875f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/990691c9aeb0/nihms942875f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/1b2b9de187ab/nihms942875f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/4b7209657abe/nihms942875f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/88ae105e6c2c/nihms942875f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/b24431208a23/nihms942875f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/7fc457374e1a/nihms942875f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/17acfb603bf5/nihms942875f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3201/5828523/990691c9aeb0/nihms942875f7.jpg

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