TY - JOUR
T1 - The E3 ligase VHL promotes follicular helper T cell differentiation via glycolytic-epigenetic control
AU - Zhu, Yangyang
AU - Zhao, Yanxia
AU - Zou, Le
AU - Zhang, Danfeng
AU - Aki, Daisuke
AU - Liu, Yun Cai
N1 - Funding Information:
We thank Drs. Y. Shi, W. Zeng, and C. Dong of Tsinghua University for providing mouse strains for this study; Dr. N. Xiao of Xiamen University (Xiamen, China) for sharing glycolytic gene profiling data; and members of the Liu laboratory for support and discussion. This work is supported by funding from the Ministry of Science and Technology of China (YFA0505802 and YFC0903900), the National Natural Science Foundation of China (NSFC81630041), and the Tsinghua-Peking Center for Life Sciences to Y-C. Liu.
Funding Information:
This work is supported by funding from the Ministry of Science and Technology of China (YFA0505802 and YFC0903900), the National Natural Science Foundation of China (NSFC81630041), and the Tsinghua-Peking Center for Life Sciences to Y-C. Liu. The authors declare no competing financial interests.
Publisher Copyright:
© 2019 Zhu et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
PY - 2019
Y1 - 2019
N2 - Follicular helper T (Tfh) cells are essential for germinal center formation and effective humoral immunity, which undergo different stages of development to become fully polarized. However, the detailed mechanisms of their regulation remain unsolved. Here we found that the E3 ubiquitin ligase VHL was required for Tfh cell development and function upon acute virus infection or antigen immunization. VHL acted through the hypoxia-inducible factor 1α (HIF-1α)−dependent glycolysis pathway to positively regulate early Tfh cell initiation. The enhanced glycolytic activity due to VHL deficiency was involved in the epigenetic regulation of ICOS expression, a critical molecule for Tfh development. By using an RNA interference screen, we identified the glycolytic enzyme GAPDH as the key target for the reduced ICOS expression via m6A modification. Our results thus demonstrated that the VHL-HIF-1α axis played an important role during the initiation of Tfh cell development through glycolytic-epigenetic reprogramming.
AB - Follicular helper T (Tfh) cells are essential for germinal center formation and effective humoral immunity, which undergo different stages of development to become fully polarized. However, the detailed mechanisms of their regulation remain unsolved. Here we found that the E3 ubiquitin ligase VHL was required for Tfh cell development and function upon acute virus infection or antigen immunization. VHL acted through the hypoxia-inducible factor 1α (HIF-1α)−dependent glycolysis pathway to positively regulate early Tfh cell initiation. The enhanced glycolytic activity due to VHL deficiency was involved in the epigenetic regulation of ICOS expression, a critical molecule for Tfh development. By using an RNA interference screen, we identified the glycolytic enzyme GAPDH as the key target for the reduced ICOS expression via m6A modification. Our results thus demonstrated that the VHL-HIF-1α axis played an important role during the initiation of Tfh cell development through glycolytic-epigenetic reprogramming.
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U2 - 10.1084/jem.20190337
DO - 10.1084/jem.20190337
M3 - Article
C2 - 31123085
AN - SCOPUS:85069266585
SN - 0022-1007
VL - 216
SP - 1664
EP - 1681
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 7
ER -