Nucleolar c‐Myc recruitment by a Vibrio T3SS effector promotes host cell proliferation and bacterial virulence

Abstract

Pathogen type 3 secretion systems (T3SS) manipulate host cell pathways by directly delivering effector proteins into host cells. In Vibrio parahaemolyticus, the leading cause of bacterial seafood‐borne diarrheal disease, we showed that a T3SS effector, VgpA, localizes to the host cell nucleolus where it binds Epstein–Barr virus nuclear antigen 1‐binding protein 2 (EBP2). An amino acid substitution in VgpA (VgpAL10A) did not alter its translocation to the nucleus but abolished the effector’s capacity to interact with EBP2. VgpA‐EBP2 interaction led to the re‐localization of c‐Myc to the nucleolus and increased cellular rRNA expression and proliferation of cultured cells. The VgpA‐EBP2 interaction elevated EBP2’s affinity for c‐Myc and prolonged the oncoprotein’s half‐life. Studies in infant rabbits demonstrated that VgpA is translocated into intestinal epithelial cells, where it interacts with EBP2 and leads to nucleolar re‐localization of c‐Myc. Moreover, the in vivo VgpA‐EBP2 interaction during infection led to proliferation of intestinal cells and heightened V. parahaemolyticus’ colonization and virulence. These observations suggest that direct effector stimulation of a c‐Myc controlled host cell growth program can contribute to pathogenesis.

TheVibrioType III Secretion System 2 is not restricted to theVibrionaceaeand encodes differentially distributed repertoires of effector proteins

“…This subgroup was primarily enriched in the VgpA effector protein, lacking most other known T3SS2 effector proteins. The presence of VgpA homologs in each subgroup supports this effector´s critical role in T3SS2 function [39,75]. As expected, the current phylotype classification (T3SS2α versus T3SS2β) was a poor predictor of the presence/absence of individual effector proteins (Fig.…”

“…Most of our knowledge of the T3SS2 comes from studies of the T3SS2α of V. parahaemolyticus strain RIMD2210633 and the T3SS2α of V. cholerae strain AM-19226 (reviewed in [18,28]). In this context, 15 different T3SS2 effector proteins have been identified, of which only 5 (VopZ, VopV, VopG, VopL and VgpA) are shared between V. parahaemolyticus RIMD2210633 and V. cholerae AM-19226 [29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]. These 5 effectors are therefore called core effector proteins, while the remaining 10 are known as accessory effector proteins [18,29,39].…”

Identification of a Family of Vibrio Type III Secretion System Effectors That Contain a Conserved Serine/Threonine Kinase Domain

“…Nine T3SS2 effector proteins in V. parahaemolyticus have been identified thus far (VopA, VopT, VopL, VopV, VopC, VopZ, VPA1380, VopO, and VgpA) ( 12 , 16 – 23 ). These effectors subvert several cellular pathways, including those controlling actin cytoskeleton dynamics and innate inflammatory responses (reviewed in references 13 , 24 , 25 ).…”

Comparative Metabolomics and Proteomics Reveal Vibrio parahaemolyticus Targets Hypoxia-Related Signaling Pathways of Takifugu obscurus

“…A previous report principally attributed this activity to the effector VgpA of the T3SS of V. parahaemolyticus. VgpA translocates into host cells and binds to EBV nuclear antigen 1-binding protein 2 (EBP2) in the nucleus (76). c-Myc, the key transcription factors controlling cell growth, metabolism and angiogenesis, form a positive feedback loop to promote cancer cell proliferation with EBP2 (77).…”