Details

Autor(en) / Beteiligte

• Zhao, Ziheng
• Wang, Yan
• Gao, Yuhan
• Ju, Yurong
• Zhao, Ye
• Wu, Zhaofei
• Gao, Shuaixin
• Zhang, Boyang
• Pang, Xuewen
• Zhang, Yu
• Wang, Wei

Titel

The PRAK-NRF2 axis promotes the differentiation of Th17 cells by mediating the redox homeostasis and glycolysis

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2023-05, Vol.120 (19), p.e2212613120-e2212613120

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• Oxidative stress is a key feature in both chronic inflammation and cancer. P38 regulated/activated protein kinase (PRAK) deficiency can cause functional disorders in neutrophils and macrophages under high oxidative stress, but the precise mechanisms by which PRAK regulates reactive oxygen species (ROS) elimination and its potential impact on CD4+ T helper subset function are unclear. The present study reveals that the PRAK-NF-E2-related factor 2(NRF2) axis is essential for maintaining the intracellular redox homeostasis of T helper 17(Th17) cells, thereby promoting Th17 cell differentiation and antitumor effects. Through mechanistic analysis, we identify NRF2 as a novel protein substrate of PRAK and find that PRAK enhances the stability of the NRF2 protein through phosphorylation NRF2 Serine(S) 558 independent of protein ubiquitination. High accumulation of cellular ROS caused by loss of PRAK disrupts both glycolysis and PKM2-dependent phosphorylation of STAT3, which subsequently impairs the differentiation of Th17 cells. As a result, knockout (KO) mice display significant resistance to experimental autoimmune encephalomyelitis (EAE) but impaired antitumor immunity in a MC38 tumor model. This work reveals that the PRAK-NRF2-mediated antioxidant pathway is a metabolic checkpoint that controls Th17-cell glycolysis and differentiation. Targeting PRAK is a promising strategy for maintaining an active ROS scavenging system and may lead to potent Th17 cell antitumor immunity.