Bacterial nucleomodulins: A coevolutionary adaptation to the eukaryotic command center

Through long-term interactions with their hosts, bacterial pathogens have evolved unique arsenals of effector proteins that interact with specific host targets and reprogram the host cell into a permissive niche for pathogen proliferation. The targeting of effector proteins into the host cell nucleus for modulation of nuclear processes is an emerging theme among bacterial pathogens. These unique pathogen effector proteins have been termed in recent years as nucleomodulins. The first nucleomodulins were discovered in the phytopathogens Agrobacterium and Xanthomonas, where their nucleomodulins functioned as eukaryotic transcription factors or integrated themselves into host cell DNA to promote tumor induction, respectively. Numerous nucleomodulins were recently identified in mammalian pathogens. Bacterial nucleomodulins are an emerging family of pathogen effector proteins that evolved to target specific components of the host cell command center through various mechanisms. These mechanisms include: chromatin dynamics, histone modification, DNA methylation, RNA splicing, DNA replication, cell cycle, and cell signaling pathways. Nucleomodulins may induce short- or long-term epigenetic modifications of the host cell. In this extensive review, we discuss the current knowledge of nucleomodulins from plant and mammalian pathogens. While many nucleomodulins are already identified, continued research is instrumental in understanding their mechanisms of action and the role they play during the progression of pathogenesis. The continued study of nucleomodulins will enhance our knowledge of their effects on nuclear chromatin dynamics, protein homeostasis, transcriptional landscapes, and the overall host cell epigenome. Author summary Bacterial pathogens have evolved a repertoire of diverse effector proteins that are secreted or injected into the host cell cytosol, reprogramming the host cell into a more favorable environment. Many of these pathogens possess nuclear-targeted effector proteins (nucleomodulins) that modulate host cell gene expression without altering the cellular genomic sequence. By utilizing nucleomodulins obtained through evolution, pathogens can manipulate host cell gene regulation and alter host immune response to infection. Here, we provide a comprehensive review discussing a diverse array of nucleomodulins that target and modulate the host genome through interference with chromatin dynamics, histone modifications, regulation of transcription, interference of the cell cycle, and regulation of cell signaling pathways for immune response. This unique targeting of host cell gene regulation through bacterial nucleomodulins is an emerging theme and likely the tip of an iceberg regarding host-pathogen interactions at the level of the host command center.

Automated summary

Bacterial pathogens have evolved unique effector proteins, termed nucleomodulins, that interact with host cells and target the host cell nucleus to regulate gene expression through various mechanisms. These nucleomodulins induce short- or long-term epigenetic modifications in host cells, influencing chromatin dynamics, transcriptional regulation, and cellular signaling pathways. Continued research on nucleomodulins will enhance our understanding of how they manipulate host cell gene regulation and alter the host cell epigenome.