The Salmonella Secreted Effector SarA/SteE Mimics Cytokine Receptor Signaling to Activate STAT3

Abstract

Highlights d The bacterial effector SarA shares sequence and function with gp130 cytokine co-receptor d Phosphorylation of SarA's YxxQ motif facilitates direct binding to STAT3 d SarA-driven STAT3 activation requires interaction with active GSK-3 d SarA has greater affinity for STAT3 than gp130 and lacks the SOCS3 interaction

A genome-wide screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation

“…These results show that GSK3 is a central regulator of the balanced host response during infection, and that targeting GSK3 function is likely to make the host susceptible to disease. In line with this prediction, GSK3 was recently found to be co-opted by the Salmonella enterica serovar Typhimurium effector SteE to skew infected macrophage polarization and allow infection to persist(65,66). Our results suggest another possible effect of targeting GSK3 may be the inefficient upregulation of MHCII on Salmonella-infected macrophages in response to IFNg.…”

JAK-ing into M1/M2 Polarization SteErs Salmonella-Containing Macrophages Away from Immune Attack to Promote Bacterial Persistence

“…JAK phosphorylation of STAT3 and STAT6 on key tyrosine residues leads to nuclear translocation and activation of downstream targets responsible for M2 polarization. In keeping with this, Panagi et al (2020) and Gibbs et al (2020) found that STAT3 (but not STAT6) was phosphorylated on its key activating tyrosine residue, Y705, in a SteE-dependent manner, but that this was independent of JAK kinases. Immunoprecipitated (IP) SteE-GFP was sufficient to phosphorylate STAT3, suggesting that SteE either acts as a cryptic kinase (which would be surprising given its small size and lack of obvious domains),or that SteE is associated with another kinase responsible for this activity (Panagi et al, 2020).…”

“…Three papers in this issue of Cell Host & Microbe now build upon these earlier findings to reveal a unique and unexpected mechanism by which SteE/SarA co-opts macrophage signaling to induce M2 polarization (Panagi et al, 2020;Gibbs et al, 2020) and demonstrate that this SteE/ SarA-mediated program counteracts a TNF-induced switch to microbicidal M1 macrophages, thus promoting Salmonella persistence within tissue granulomas (Pham et al, 2020).…”

“…Notably, coIP mass-spectrometry analyses revealed the association of SteE with both alpha and beta isoforms of the serine/threonine kinase glycogen synthase kinase 3 (GSK3a and GSK3b) (Figure 1). Deletion of GSK3a and GSK3b (but not either alone), or pharmacological inhibition of GSK3, abrogated STAT3 phosphorylation of Y705, demonstrating a key functional requirement for GSK3 in SteE/SarAdependent phosphorylation of STAT3 (Panagi et al, 2020;Gibbs et al, 2020). Of note, SteE/SarA itself was phosphorylated by GSK3 on a tyrosine residue located at the C terminus of the protein in its ''YIAQ'' sequence, which closely resembles the YxxQ motif in the gp130 subunit of IL-6R that binds to STAT3 (Gibbs et al, 2020).…”

“…Deletion of GSK3a and GSK3b (but not either alone), or pharmacological inhibition of GSK3, abrogated STAT3 phosphorylation of Y705, demonstrating a key functional requirement for GSK3 in SteE/SarAdependent phosphorylation of STAT3 (Panagi et al, 2020;Gibbs et al, 2020). Of note, SteE/SarA itself was phosphorylated by GSK3 on a tyrosine residue located at the C terminus of the protein in its ''YIAQ'' sequence, which closely resembles the YxxQ motif in the gp130 subunit of IL-6R that binds to STAT3 (Gibbs et al, 2020). Moreover, phosphorylation of this tyrosine was required for STAT3 binding, indicating that SteE Salmonella-containing granulomas (left) harbor heterogenous populations of macrophages that express inflammatory, or M1-like (high TNF, iNOS), and immunomodulatory, or M2-like (high IL-4Ra, CD301), markers.…”