NleB, a Bacterial Effector with Glycosyltransferase Activity, Targets GAPDH Function to Inhibit NF-κB Activation

Abstract

Summary Modulation of NF-κB-dependent responses is critical to the success of attaching/effacing (A/E) human pathogenic E. coli (EPEC and EHEC) and the natural mouse pathogen Citrobacter rodentium. NleB, a highly conserved type III secretion system effector of A/E pathogens, suppresses NF-κB activation, but the underlying mechanisms are unknown. We identified the mammalian glycolysis enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an NleB interacting protein. Further, we discovered that GAPDH interacts with the TNF receptor associated factor 2 (TRAF2), a protein required for TNF-α-mediated NF-κB activation, and regulates TRAF2 polyubiquitination. During infection, NleB functions as a translocated N-acetyl-D-glucosamine (O-GlcNAc) transferase that modifies GAPDH. NleB-mediated GAPDH O-GlcNAcylation disrupts the TRAF2-GAPDH interaction to suppress TRAF2 polyubiquitination and NF-κB activation. Eliminating NleB O-GlcNAcylation activity attenuates C. rodentium colonization of mice. These data identify GAPDH as a TRAF2 signaling cofactor and reveal a virulence strategy employed by A/E pathogens to inhibit NF-κB dependent host innate immune responses.

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

“…[141][142][143][144][145] In addition, the mouse pathogen Citrobacter rodentium, which imitates EPEC, delivers the effector NleB to O-GlcNAcylate, the host glyceraldehyde 3-phosphate dehydrogenase, thus disrupting its interaction with TRAF2 and arresting the NF-κB pathway. 146 …”

Modulation of Gene Expression Regulated by the Transcription Factor NF-κB/RelA

“…Recently, it has been reported that the mechanism is related to the role of GAPDH in TNF-induced NF-B activation (45). This function may be disrupted during pathogen infection as an important virulence strategy used by attaching/ effacing pathogens to inhibit the host NF-B-dependent innate immune responses.…”

Cytoplastic Glyceraldehyde-3-Phosphate Dehydrogenases Interact with ATG3 to Negatively Regulate Autophagy and Immunity in Nicotiana benthamiana

“…In animal cells, GAPDH participates in multiple nonmetabolic processes, including apoptosis activation, S phase-dependent histone H2B transcription, DNA replication, DNA repair, and immune response to various diseases (Sirover, 1997;Zheng et al, 2003;Hara et al, 2005;Bae et al, 2006;Harada et al, 2007). GAPDH is also involved in NF-kB-dependent host innate immune responses, while pathogen effector NieB mediates O-GlcNAcylation of GAPDH to disrupt the TRAF2-GAPDH interaction and further suppresses TRAF2 polyubiquitination and NF-kB activation (Gao et al, 2013). In plants, GAPDHs have been implicated in embryo development, pollen development, root growth, lipid metabolism, seed oil accumulation, and abscisic acid signal transduction (Rius et al, 2006(Rius et al, , 2008Muñoz-Bertomeu et al, 2009Kim et al, 2013;Guo et al, 2014).…”