Bacterial nucleomodulins: A coevolutionary adaptation to the eukaryotic command center

Abstract

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.

Fig 1. Strategies utilized by nucleomodulins to enter the nucleus and modulate host cell response and gene expression.

Nucleomodulins can enter the nucleus by (A) diffusion through nuclear pores, (B) using an NLS to interact with the nuclear pore complex for import, (C) hijacking host proteins in the cytosol containing an NLS that localize to the nucleus, or (D) currently unknown mechanisms. After entry into the nucleus, nucleomodulins can modulate the host cell epigenome by (1) altering the nuclear ubiquitination and signaling pathways, (2) dysregulating protein localization and accumulation in the nucleus or nucleolus, and/or (3) directly targeting and modifying host DNA and histones. NLS, nuclear localization signal.