SIK2 orchestrates actin-dependent host response upon <i>Salmonella</i> infection

Abstract

<i>Salmonella</i> is an intracellular pathogen of a substantial global health concern. In order to identify key players involved in <i>Salmonella</i> infection, we performed a global host phosphoproteome analysis subsequent to bacterial infection. Thereby, we identified the kinase SIK2 as a central component of the host defense machinery upon <i>Salmonella</i> infection. SIK2 depletion favors the escape of bacteria from the <i>Salmonella</i>-containing vacuole (SCV) and impairs Xenophagy, resulting in a hyperproliferative phenotype. Mechanistically, SIK2 associates with actin filaments under basal conditions; however, during bacterial infection, SIK2 is recruited to the SCV together with the elements of the actin polymerization machinery (Arp2/3 complex and Formins). Notably, SIK2 depletion results in a severe pathological cellular actin nucleation and polymerization defect upon <i>Salmonella</i> infection. We propose that SIK2 controls the formation of a protective SCV actin shield shortly after invasion and orchestrates the actin cytoskeleton architecture in its entirety to control an acute <i>Salmonella</i> infection after bacterial invasion.