Bidirectional regulation between AP-1 and SUMOylation pathway genes modulates inflammatory signaling duringSalmonellainfection

Abstract

Post-translational modifications (PTMs), such as SUMOylation, are known to modulate fundamental processes of a cell. Infectious agents such as Salmonella Typhimurium (STm) that causes gastroenteritis, utilizes PTM mechanism SUMOylation to highjack host cell. STm suppresses host SUMO-pathway genes Ubc9 and PIAS1 to perturb SUMOylation for an efficient infection. In the present study, the regulation of SUMO-pathway genes during STm infection was investigated. A direct binding of c-Fos, a component of AP-1 (Activator Protein-1), to promoters of both UBC9 and PIAS1 was observed. Experimental perturbation of c-Fos led to changes in expression of both Ubc9 and PIAS1. STm infection of fibroblasts with SUMOylation deficient c-Fos (c-FOS-KOSUMO-def-FOS) resulted in uncontrolled activation of target genes, resulting in massive immune activation. Infection of c-FOS-KOSUMO-def-FOS cells favored STm replication, indicating misdirected immune mechanisms. Finally, chromatin Immuno-precipitation assays confirmed a context dependent differential binding and release of AP-1 to/from target genes due to its Phosphorylation and SUMOylation respectively. Overall, our data point towards existence of a bidirectional cross-talk between c-Fos and the SUMO pathway and highlighting its importance in AP-1 function relevant to STm infection and beyond.