RNA Binding Proteins PCBP1 and PCBP2 Impact Posttranscriptional Control of the Erythroid Lineage
The RNA binding proteins PCBP1 and PCBP2 are each essential for mouse development. Ji et al. (e00668-20) used conditional gene knockouts to explore roles of PCBP1 and PCBP2 in erythroid development. Ablation of each individual protein during erythroid differentiation in the mouse embryo failed to impact viability or blood formation, while their combined loss triggered midgestational repression of hematopoietic gene expression, loss of blood formation, and fetal demise. Orthogonal analyses in primary erythroid progenitors revealed that the two proteins mediate overlapping and isoform-specific impacts on the hematopoietic transcriptome. These data reveal that PCBPs play complex and essential roles in mammalian erythropoiesis.
Cyclin-Dependent Kinase 8 (CDK8) Inhibition Reveals a CDK8-GATA3-FOXP3 Pathway Regulating Tolerogenicity in CD4+ T Cells
Cyclin-dependant kinase 8 (CDK8), a facultative component of the Mediator complex, is emerging as an important immunomodulator. Inhibition of CDK8 promotes tolerogenicity in both myeloid (pro-interleukin-10 [pro-IL-10]) and CD4+ T cells (pro-Treg differentiation). Arnett et al. (e00085-21) demonstrate that CDK8 broadly regulates Treg/Th2/Th1/Th17 differentiation and describe a novel unifying human-relevant mechanism. They demonstrate that CDK8 inhibits Gata3 expression, as well as early Foxp3 expression. Furthermore, they show that under pro-Treg conditions, GATA3 can drive FOXP3 expression and Treg differentiation. These findings highlight CDK8 as a druggable regulator of tolerogenicity impacting different effector pathways in myeloid (c-Jun) versus CD4+ T cells.