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- Title
Human IL-17A protein production is controlled through a PIP5K1α-dependent translational checkpoint.
- Authors
Revu, Shankar K.; Yang, Wenjuan; Rajasundaram, Dhivyaa; Brady, Alexander; Majumder, Saikat; Gaffen, Sarah L.; Hawse, William; Xia, Zongqi; McGeachy, Mandy J.
- Abstract
The cytokine interleukin-17 (IL-17) is secreted by T helper 17 (TH17) cells and is beneficial for microbial control; however, it also causes inflammation and pathological tissue remodeling in autoimmunity. Hence, TH17 cell differentiation and IL-17 production must be tightly regulated, but, to date, this has been defined only in terms of transcriptional control. Phosphatidylinositols are second messengers produced during T cell activation that transduce signals from the T cell receptor (TCR) and costimulatory receptors at the plasma membrane. Here, we found that phosphatidylinositol 4,5-bisphosphate (PIP2) was enriched in the nuclei of human TH17 cells, which depended on the kinase PIP5K1α, and that inhibition of PIP5K1α impaired IL-17A production. In contrast, nuclear PIP2 enrichment was not observed in TH1 or TH2 cells, and these cells did not require PIP5K1α for cytokine production. In T cells from people with multiple sclerosis, IL-17 production elicited by myelin basic protein was blocked by PIP5K1α inhibition. IL-17 protein was affected without altering either the abundance or stability of IL17A mRNA in TH17 cells. Instead, analysis of PIP5K1α-associating proteins revealed that PIP5K1α interacted with ARS2, a nuclear cap-binding complex scaffold protein, to facilitate its binding to IL17A mRNA and subsequent IL-17A protein production. These findings highlight a transcription-independent, translation-dependent mechanism for regulating IL-17A protein production that might be relevant to other cytokines. Editor's summary: Interleukin-17 (IL-17)–producing CD4+ helper T (TH17) cells are important for immune responses to infections but also mediate chronic inflammation in autoimmune diseases. Revu et al. uncovered a nuclear role for the phospholipid PIP2 in IL-17 production by TH17 cells. During the differentiation of human naïve CD4+ T cells into TH17 cells in vitro, PIP2 was enriched in nuclei, which required the kinase PIP5K1α and which facilitated the translation of IL17A mRNA and IL-17 protein production. Treatment of CD4+ T cells isolated from patients with multiple sclerosis with a PIP5K1α inhibitor reduced their secretion of IL-17A, suggesting that this pathway might be therapeutically targeted to treat autoimmune diseases. —John F. Foley
- Subjects
SCAFFOLD proteins; MYELIN basic protein; T cell receptors; T cells; PROTEINS; CD28 antigen; TISSUE remodeling
- Publication
Science Signaling, 2023, Vol 16, Issue 808, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abo6555