Ehrlichia TRP effectors: moonlighting, mimicry and infection

Abstract

Intracellular bacteria have evolved various strategies to evade host defense mechanisms. Remarkably, the obligately intracellular bacterium, Ehrlichia chaffeensis, hijacks host cell processes of the mononuclear phagocyte to evade host defenses through mechanisms executed in part by tandem repeat protein (TRP) effectors secreted by the type 1 secretion system. In the past decade, TRP120 has emerged as a model moonlighting effector, acting as a ligand mimetic, nucleomodulin and ubiquitin ligase. These defined functions illuminate the diverse roles TRP120 plays in exploiting and manipulating host cell processes, including cytoskeletal organization, vesicle trafficking, cell signaling, transcriptional regulation, post-translational modifications, autophagy and apoptosis. This review will focus on TRP effectors and their expanding roles in infection and provide perspective on Ehrlichia chaffeensis as an invaluable model organism for understanding infection strategies of obligately intracellular bacteria.

Keywords: Ehrlichia chaffeensis; effector proteins; effector–pathogen interactions; intracellular bacteria; moonlighting; tandem repeat proteins.

Figure 1.

E. chaffeensis TRP effectors. Schematic of E. ch. TRPs illustrating TR domains and other important features. TRPs contain molecularly distinct TR domains that vary in sequence, length and number. TRPs are secreted by the T1SS and have predicted type 1 secretion signals located in the terminal amino acids of the C-terminal domain. The TRP effectors are nucleomodulins that bind host cell DNA via TR DNA binding domains to modulate host gene transcription. TRPs are modified by PTMs and sites of ubiquitination, SUMOylation and phosphorylation have been identified. TRP120 is a HECT E3 ubiquitin ligase and contains a conserved catalytic site in the C-terminal domain, allowing it to ubiquitinate and target host proteins for degradation.

Figure 2.

TRP120 exploitation of host PTM pathways and host protein interactions. TRP120 is SUMOylated at canonical SUMO motif by host cell PTM machinery (UBC9), which promotes the direct interaction between Myo10 and GGA1. TRP120 auto-ubiquitinates via intrinsic HECT E3 Ub ligase activity and interacts with host NEDD4L to mediate self-ubiquitination. In the nucleus, TRP120 uses Ub ligase activity to target FBW7and PCGF5 for Ub-mediated degradation. TRP120 binds to FBW7 in a trans conformation and ubiquitinates with K48-Ub chains, resulting in the upregulation of Notch genes and oncoproteins for cell survival. SUMOylated TRP120 binds PCGF5 resulting in PCGFs degradation and the upregulation of HOX genes.

Figure 3.

TRP-mediated activation of conserved signaling pathways and role in infection. TRPs act as ligand mimetics and interact with Notch and Wnt receptors to activate host cell signaling. On the cell surface, E.ch. TRP120 expressed on the surface of dense-cored ehrlichiae interacts with ADAM17 and possibly Notch receptor to activate Notch signaling. Similarly, TRP120 interacts with FZD receptors to activate canonical and non-canonical Wnt signaling to regulate apoptosis and autophagy. Notably, expression of the FZD5 receptor increases during infection. In addition, TRP32 interactions with Wnt transcription factor DAZAP2 to potentially influence Wnt gene transcription.