FoxP3 forkhead dimer: Don't swap me now.

FoxP3 is critical for regulatory T cell function and, thus, overall immune homeostasis. In this issue of Immunity, Leng et al. reveal how FoxP3 achieves specific recognition of DNA and functional specialization by adopting a head-to-head domain conformation.

Yersinia remodels epigenetic histone modifications in human macrophages.

Various pathogens systematically reprogram gene expression in macrophages, but the underlying mechanisms are largely unknown. We investigated whether the enteropathogen Yersinia enterocolitica alters chromatin states to reprogram gene expression in primary human macrophages. Genome-wide chromatin immunoprecipitation (ChIP) seq analyses showed that pathogen-associated molecular patterns (PAMPs) induced up- or down-regulation of histone modifications (HMod) at approximately 14500 loci in promoters and enhancers. Effectors of Y. enterocolitica reorganized about half of these dynamic HMod, with the effector YopP being responsible for about half of these modulatory activities. The reorganized HMod were associated with genes involved in immune response and metabolism. Remarkably, the altered HMod also associated with 61% of all 534 known Rho GTPase pathway genes, revealing a new level in Rho GTPase regulation and a new aspect of bacterial pathogenicity. Changes in HMod were associated to varying degrees with corresponding gene expression, e. g. depending on chromatin localization and cooperation of the HMod. In summary, infection with Y. enterocolitica remodels HMod in human macrophages to modulate key gene expression programs of the innate immune response.

The structure of human SFPQ reveals a coiled-coil mediated polymer essential for functional aggregation in gene regulation.

SFPQ, (a.k.a. PSF), is a human tumor suppressor protein that regulates many important functions in the cell nucleus including coordination of long non-coding RNA molecules into nuclear bodies. Here we describe the first crystal structures of Splicing Factor Proline and Glutamine Rich (SFPQ), revealing structural similarity to the related PSPC1/NONO heterodimer and a strikingly extended structure (over 265 Å long) formed by an unusual anti-parallel coiled-coil that results in an infinite linear polymer of SFPQ dimers within the crystals. Small-angle X-ray scattering and transmission electron microscopy experiments show that polymerization is reversible in solution and can be templated by DNA. We demonstrate that the ability to polymerize is essential for the cellular functions of SFPQ: disruptive mutation of the coiled-coil interaction motif results in SFPQ mislocalization, reduced formation of nuclear bodies, abrogated molecular interactions and deficient transcriptional regulation. The coiled-coil interaction motif thus provides a molecular explanation for the functional aggregation of SFPQ that directs its role in regulating many aspects of cellular nucleic acid metabolism.

A bacterial effector protein promotes nuclear translocation of Stat3 to induce IL-10.

The multifunctional Yersinia effector YopM inhibits effector triggered immunity and increases production of the anti-inflammatory cytokine Interleukin-10 (IL-10) to suppress the host immune response. Previously it was shown that YopM induces IL-10 gene expression by elevating phosphorylation of the serine-threonine kinase RSK1 in the nucleus of human macrophages. Using transcriptomics, we found that YopM strongly affects expression of genes belonging to the JAK-STAT signaling pathway. Further analysis revealed that YopM mediates nuclear translocation of the transcription factor Stat3 in Y. enterocolitica infected macrophages and that knockdown of Stat3 inhibited YopM-induced IL-10 gene expression. YopM-induced Stat3 translocation did not depend on autocrine IL-10, activation of RSK1 or tyrosine phosphorylation of Stat3. Thus, besides activation of RSK1, stimulation of nuclear translocation of Stat3 is another mechanism by which YopM increases IL-10 gene expression in macrophages.