A central role for STAT5 in the transcriptional programing of T helper cell metabolism

Abstract

Activated lymphocytes adapt their metabolism to meet the energetic and biosynthetic demands imposed by rapid growth and proliferation. Common gamma chain (cγ) family cytokines are central to these processes, but the role of downstream signal transducer and activator of transcription 5 (STAT5) signaling, which is engaged by all cγ members, is poorly understood. Using genome-, transcriptome-, and metabolome-wide analyses, we demonstrate that STAT5 is a master regulator of energy and amino acid metabolism in CD4 + T helper cells. Mechanistically, STAT5 localizes to an array of enhancers and promoters for genes encoding essential enzymes and transporters, where it facilitates p300 recruitment and epigenetic remodeling. We also find that STAT5 licenses the activity of two other key metabolic regulators, the mTOR signaling pathway and the MYC transcription factor. Building on the latter, we present evidence for transcriptome-wide cooperation between STAT5 and MYC in both normal and transformed T cells. Together, our data provide a molecular framework for transcriptional programing of T cell metabolism downstream of cγ cytokines and highlight the JAK-STAT pathway in mediating cellular growth and proliferation.

STAT5 Gain-of-Function Variants Promote Precursor T-Cell Receptor Activation to Drive T-Cell Acute Lymphoblastic Leukemia

“…6A ). While PIM1 and BCL2 are STAT5 target genes, BCL-2 is also independently regulated by the PI3K/AKT/mTOR pathway, which is in turn interwoven with STAT5 signaling in T-cell metabolism (45,56). T-ALL cells with high STAT5 activation were sensitive to JPX-0750 compared to control lung adenocarcinoma A549 cells ( Fig.…”

Transcriptional programing of T cell metabolism by STAT family transcription factors

“…Its role in T cell metabolism has been studied for over 30 years but, as noted, that research has traditionally focused on downstream PI3-AKT and mTOR signaling. However, it is now apparent that STAT5 is also critical and, in fact, required for parallel mTOR activity [30]. For details on how PI3-AKT and mTOR influence cellular metabolism, we refer to comprehensive reviews [31,46].…”

“…In almost all cases, there is evidence that downstream STAT5 signaling instructs expression of relevant transporters, such as GLUT1, SLC1A5, the principal transporter for glutamine, and SLC7A5, the principal transporter for essential amino acids (Fig. 1) [30,45,48,49]. Second, IL-2 rapidly and potently induces glycolysis, glutaminolysis, and OxPhos, enabling cells to burn their newly obtained fuels [47,50,51].…”

“…Second, IL-2 rapidly and potently induces glycolysis, glutaminolysis, and OxPhos, enabling cells to burn their newly obtained fuels [47,50,51]. Several enzymes in these pathways are directly regulated by STAT5 [30]. Third, IL-2 promotes macromolecule synthesis, thereby providing necessary building blocks for cellular growth and proliferation.…”

“…1). In fact, paired surveys of genome‐wide STAT occupancy (by ChIP‐seq) and STAT‐dependent gene expression (by RNA‐seq) have established that hundreds of metabolism‐related genes may be subject to direct transcriptional control in CD4 + T cells [26–30]. This is in contrast to the PI3K‐AKT and mTOR pathways, which mainly operate by posttranscriptional mechanisms [31, 32], but in line with the idea that transcriptional regulation of metabolism is also crucial [8].…”