Orientia tsutsugamushi targets lamin A using Ank effectors and alters chromatin to inhibit NF-κB

Nuclear factor-κB (NF-κB) nuclear localization and gene accessibility is mediated by Ser22-phosphorylated lamin A/C (pSer22-lamin A/C). Here, we report that the intracellular bacterium Orientia tsutsugamushi impairs NF-κB nuclear accumulation by targeting lamin A using multiple ankyrin repeat (AR)-containing effectors (Anks). The Anks' immunomodulatory capability requires a conserved hydrophilic α-helical peptide that binds lamin A/pSer22-lamin A and lies between the AR and PRANC (pox proteins repeats of ankyrin C-terminal) domains. Orientia promotes pSer22-lamin A redistribution from the lamina to the nucleoplasm. This phenotype can be recapitulated in uninfected cells by ectopically expressing Anks that carry the lamin A-binding sequence. O. tsutsugamushi also alters chromatin accessibility at sites regulated by lamin A, NF-κB, and the NF-κB coactivator, adapter protein 1. These findings identify a mechanism by which a pathogen synergistically modulates lamin A and chromatin accessibility to counteract NF-κB, reinforce the regulatory link between lamin A and NF-κB, and indicate that pSer22-lamin A enhances chromatin accessibility to NF-κB and its coactivators.