The ability of Salmonella Typhimurium to exploit macrophages as a niche for survival, replication, and dissemination is central to its pathogenesis. The effector SteE, which polarizes macrophages into an anti-inflammatory state, is critical during invasive disease. SteE operates via an unprecedented mechanism, reprogramming the host serine/threonine kinase GSK3 to perform tyrosyl-directed phosphorylation of neosubstrates, including the immune transcription factors STAT1 and STAT3. Here, we demonstrate that SteE-driven transcriptional reprogramming relies critically and specifically on STAT3 phosphorylation and DNA binding. By activating STAT3 via a non-canonical pathway, bypassing endogenous negative feedback mechanisms, SteE drives hyperactivation of STAT3 target genes, surpassing the effects of canonical IL-10 signaling. Hyperactivation correlates with elevated phosphorylated STAT3 in the macrophage nucleus and coordinated chromatin remodeling at STAT3 target loci. Overall, our study illustrates how hijacking of a signaling pathway by SteE dramatically reshapes the macrophage gene regulatory network to enhance Salmonella immune evasion. • Macrophage polarization by Salmonella effector SteE relies critically on STAT3 • SteE drives hyperactivation of STAT3 target genes • Hyperactivation correlates with elevated STAT3 activation and chromatin remodeling • SteE induces opening of chromatin regions not accessible during IL-10 stimulation Diaz-del-Olmo et al. reveal how a Salmonella virulence protein alters the transcriptional layout of infected macrophages through hyperactivation of a transcription factor and coordinated chromatin remodeling.
Diaz-del-Olmo et al. (Fri,) studied this question.