The AP-1 factorsFOSL1andFOSL2co-regulate human Th17 responses

Abstract

Th17 cells protect mucosal barriers, but their aberrant activity can cause autoimmunity. Molecular networks dictating human Th17 function are largely unexplored, and this hinders disease-studies. Here, we investigated the functions of the AP-1 proteins FOSL1 and FOSL2 in inducing human Th17 responses. Transient knockdown and over-expression strategies demonstrated the two proteins to inhibit Th17-cell identity, while revealing a novel cooperativity between their functions. Strikingly, FOSL1 plays different roles in human and mouse and FOSL-mediated Th17 regulation is opposed by the AP-1 factor, BATF. Genome- wide occupancy analysis indicated the co-localization of FOSL1, FOSL2 and BATF in the proximity of key Th17 genes. The functional interplay among these transcription factors (TFs) is potentially governed by sharing interactions with a common set of lineage-associated proteins. We further discovered that the genomic binding sites of these factors harbor a large number of disease-linked SNPs, many of which alter the ability of a given factor to bind DNA. Our findings thus provide crucial insights into the pathology of Th17-mediated diseases.

Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells

“…Prediction models have indicated that interaction partners shared by candidate TFs could facilitate co-operative or competitive tendencies between the factors . Our recent study revealed a functional coordination between FOSL1 and FOSL2 during human Th17 regulation . To investigate whether an interactome-based mechanism regulates this paradigm, we analyzed these factors for their common binding partners.…”

“…AP-1 function is highly complex and is systematically regulated at multiple levels, such as, the choice of dimerizing partner, post-transcriptional/translational events, and additional interactions with bZIP or other unrelated proteins. Our recent functional genomics study found FOSL1 and FOSL2 to negatively regulate human Th17 differentiation . To decipher the mechanisms that govern such functions of FOSL proteins, we examined their binding partners using a whole-cell proteomics approach.…”

“…This process is also modulated by members of the activator protein (AP-1) family, which includes the JUN (JUNB , ), FOS (FOSL1, FOSL2), and ATF (BATF, ATF3) proteins. FOSL1 and FOSL2 (collectively termed FOS-like proteins) are two paralogous TFs that regulate embryonic development, cancer progression, and immune cell signaling. − Their significance in initiating murine Th17 responses, however, was only recently realized. , Though molecular networks are highly conserved in humans and mice, genetic studies across the two species have revealed striking discrepancies. ,− In light of this, a parallel study from our laboratory used cord blood T cells to verify the human-specific roles of FOSL1 and FOSL2 in Th17-regulation . Functional genomics approaches revealed both of these factors to negatively influence Th17 responses in humans .…”

“…5,19−23 In light of this, a parallel study from our laboratory used cord blood T cells to verify the human-specific roles of FOSL1 and FOSL2 in Th17regulation. 24 Functional genomics approaches revealed both of these factors to negatively influence Th17 responses in humans. 24 Nonetheless, the molecular mechanisms that mediate these effects are not understood.…”

“…24 Functional genomics approaches revealed both of these factors to negatively influence Th17 responses in humans. 24 Nonetheless, the molecular mechanisms that mediate these effects are not understood.…”