Cells contain a reservoir of inactive GEF-H1 bound to microtubules that is activated by dephosphorylation to form signaling platforms for the activation of innate and cell-autonomous immunity. Muramyl-dipeptide (MDP) is the minimal structural motif of peptidoglycan of both Gram-positive and Gram-negative bacteria and the functional component of Freud’s adjuvant used to boost vaccination responses. Genome-wide transcriptome analysis revealed that much of the transcriptional response to MDP in macrophages dependents on GEF-H1. Our efforts to identify the responsible transcription factor identified interferon regulatory factor 5 (IRF5) as essential for the control of host responses to MDP. In this pathway, GEF-H1 has an essential role in the activation of IKKε that has a critical function as an upstream IKKα/β and IRF5 kinase. Identification of the GEF-H1-IKKε-IRF5 pathway has wide-reaching implications beyond direct microbial defense as polymorphisms in the IRF5 gene have been linked to human autoimmune diseases. Excitingly, GEF-H1 mediated host defenses are not limited to the cells of the immune system as many cells throughout the body express GEF-H1 and therefore could mount cell-autonomous immune responses through this pathway.
The GEFH1 immune activation pathway.
