Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins

Abstract

Pathogenic bacteria secrete a variety of proteins that manipulate host cell function by targeting components of the plasma membrane, cytosol, or organelles. In the last decade, several studies identified bacterial factors acting within the nucleus on gene expression or other nuclear processes, which has led to the emergence of a new family of effectors called "nucleomodulins". In human and animal pathogens, Listeria monocytogenes for Gram-positive bacteria and Anaplasma phagocytophilum, Ehrlichia chaffeensis, Chlamydia trachomatis,Legionella pneumophila, Shigella flexneri, and Escherichia coli for Gram-negative bacteria, have led to pioneering discoveries. In this review, we present these paradigms and detail various mechanisms and core elements (e.g., DNA, histones, epigenetic regulators, transcription or splicing factors, signaling proteins) targeted by nucleomodulins. We particularly focus on nucleomodulins interacting with epifactors, such as LntA of Listeria and ankyrin repeat- or tandem repeat-containing effectors of Rickettsiales, and nucleomodulins from various bacterial species acting as post-translational modification enzymes. The study of bacterial nucleomodulins not only generates important knowledge about the control of host responses by microbes but also creates new tools to decipher the dynamic regulations that occur in the nucleus. This research also has potential applications in the field of biotechnology. Finally, this raises questions about the epigenetic effects of infectious diseases.

Keywords: Listeria; effectors; epigenetics; nucleomodulin; nucleus; pathogens.

Figure 1

Nucleomodulins of L. monocytogenes, A. phagocytophilum, and E. chaffeensis. Listeria in the cytosol and Anaplasma or Ehrlichia within vacuoles secrete nucleomodulins (in green) that enter into the nucleus (represented by an orange oval; blue cylinders labeled “H” represent histones; host nuclear factors are in yellow). Post-translational modifications (PTMs): acetylation (Ac), ubiquitination (Ub). (A) L. monocytogenes secretes two nucleomodulins. LntA inhibits the binding of a BAHD1–HDAC chromatin repressive complex to ISG promoters, thus promoting histone acetylation and activation of ISG expression and stimulating interferon responses. OrfX decreases RYBP amounts, which impairs P53-mediated activation of the oxidative stress response and potentially PRC1-mediated regulation. (B) A. phagocytophilum AnkA binds to AT-rich DNA motifs and recruits HDAC1 at the CYBB promoter, thus promoting histone deacetylation and repression of CYBB and altering the function of NAPDH oxidase. AnkA also binds to nuclear matrix attachment regions (MARs) throughout the genome. (C) E. chaffeensis secretes four nucleomodulins. Ank200 binds to Alu-Sx DNA motifs, while TRP32, TRP47, and TRP120 bind to G-rich or G + C-rich DNA motifs, as well as to a set of transcriptional regulators and epifactors, leading to deregulation of many host genes with multiple functions. In particular, TRP120 interacts with PCGF5 of the PRC1 complex. Delocalization and ubiquitination of PCGF5 by TRP120 at the ehrlichial vacuole is proposed to inhibit PRC1-mediated repression of a set of host genes.

Figure 2

Nucleomodulins of L. pneumophila, M. tuberculosis (Mtb), S. flexneri, and E. coli. Legionella or Mtb within vacuoles and S. flexneri or E. coli from the extracellular compartment (or the entry vacuole, for Shigella) secrete nucleomodulins (in green) that enter into the nucleus (represented by an orange oval; blue cylinders labeled “H” represent histones; host nuclear factors are in yellow). PTMs: acetylation (Ac), methylation (Me), phosphorylation (P), eliminylation (E), ubiquitination (Ub), deamination (Da). (A) L. pneumophila secretes four nucleomodulins. The histone methyltransferase RomA/LegAS4 triggers H3K14me3 at specific gene promoters, and thus, transcriptional repression of a network of immune defense genes. An additional function was described for LegAS4 in the nucleolus, where it binds to HP1 at rDNA promoters and activates rDNA gene expression. AnkH interacts with LARP7, a component of the 7SK snRNP complex, and interferes with transcriptional elongation by RNA Pol II. SnlP interferes with RNA Pol II by inhibiting the transcription elongation factor SUPT5H. AnkX interacts with PLEKHN1 but the function of this interaction is unknown. (B) M. tuberculosis (MTB) secretes three nucleomodulins playing a role in the deregulation of immune defense gene expression. Rv1988 is a histone methyltransferase that triggers H3R42me2. Rv3423 is a histone acetyltransferase. Rv2966c is a DNA methyltransferase. (C) S. flexneri secretes four nucleomodulins. OspF induces elimination of mitogen activated protein (MAP)-kinases in the nucleus, thus preventing phosphorylation of histone H3 on serine 10 and inducing repression of a subset of immune defense genes. OspF also binds the retinoblastoma protein (Rb), as another effector, OspB. IpaH9.8 ubiquitinylates and promotes degradation of the splicing factor U2AF³⁵. IpaB has pleiotropic functions, one of which involves Mad2L2, an inhibitor of the APC^cdh1/C ubiquitin ligase complex. IpaB interaction with Mad2L2 promotes unscheduled activation of APC and premature degradation of several cell cycle proteins. (D) E. coli secretes four nucleomodulins. NleG5-1 ubiquitinylates and promotes degradation of the mediator complex component MED15. Cif deamidates NEDD8 in the CULLIN subunit of SCF ubiquitin ligase complexes, thus preventing SCF-mediated degradation of cell cycle regulators. NleC is a metalloproteinase targeting histone acetyltransferase (HAT) p300 for degradation. EspF targets the nucleolus and causes loss of nucleolin.