Modulation of NF-κB signalling by microbial pathogens

Abstract

The nuclear factor-κB (NF-κB) family of transcription factors plays a central part in the host response to infection by microbial pathogens, by orchestrating the innate and acquired host immune responses. The NF-κB proteins are activated by diverse signalling pathways that originate from many different cellular receptors and sensors. Many successful pathogens have acquired sophisticated mechanisms to regulate the NF-κB signalling pathways by deploying subversive proteins or hijacking the host signalling molecules. Here, we describe the mechanisms by which viruses and bacteria micromanage the host NF-κB signalling circuitry to favour the continued survival of the pathogen.

Figure 1. The classical and alternative NF-κB signalling pathways use a wide variety of signals to control a diverse set of cellular responses

Protein levels and activity of signalling molecules can be regulated through post-translational modifications such as phosphorylation, ubiquitylation and acetylation. The activation of nuclear factor-κB (NF-κB) ultimately results in the transcription of genes that encode pro-inflammatory factors and factors that influence cell proliferation. IκBα, NF-κB inhibitor-α (also known as NF-κBIα); IKK, IκB kinase; IL-1R, interleukin-1 receptor; NEMO, NF-κB essential modulator (also known as IKKγ); NIK, NF-κB-inducing kinase (also known as MAP3K14); TLR, Toll-like receptor; TNFR, TNF receptor.

Figure 2. Activation of NF-κB signalling pathways by microbial pathogens

A diagrammatic representation of the nuclear factor-κB (NF-κB) pathways that are induced by various receptors, microbial pathogens and pathogen-derived proteins. See main text for details. Virus-encoded proteins are in green boxes, and bacterium- and parasite-encoded proteins are in orange boxes. ASFV, African swine fever virus; BFV, bovine foamy virus; B. pertussis, Bordetella pertussis; CRL, cullin-RING ubiquitin ligase; EBV, Epstein–Barr virus; FHA, filamentous haemagglutinin; gp350, glycoprotein 350; HBV, hepatitis B virus; HCV, hepatitis C virus; HSV, herpes simplex virus; HSVA, herpesvirus ateles; HSVS, herpesvirus saimiri; HTLV-1, human T cell leukaemia virus 1; IκBα, NF-κB inhibitor-α (also known as NF-κBIα); IKK, IκB kinase; IRAK, IL-1R-associated kinase; KSHV, Kaposi’s sarcoma-associated herpesvirus; LMP1, latent membrane protein 1; L. pneumophila, Legionalla pneumophila; MYD 88, myeloid differentiation primary response protein 88; NEMO, NF-κB essential modulator (also known as IKKγ); RIP1, receptor-interacting protein 1 (also known as RIPK1); R. rickettsii, Rickettsia rickettsii; RSV, respiratory syncytial virus; SCF^βTRCP, SKP1, cullin 1 and F-box protein βTRCP; S. flexneri, Shigella flexneri; Stp, Saimiri transformation-associated protein; TAK1, TGFβ-activated kinase 1; T. gondii, Toxoplama gondii; TLR, Toll-like receptor; TNFR, TNF receptor; TRAF, TNFR-associated factor; Ub, ubiquitin.

Figure 3. Inhibition of NF-κB signalling pathways by microbial pathogens

A diagrammatic representation of the nuclear factor-κB (NF-κB) pathways, showing the signalling molecules that are targeted by microbial pathogen-derived proteins for inhibition of the NF-κB pathways. See main text for details. Virus-encoded proteins are in green boxes, and bacterium-encoded proteins are in orange boxes. Ac, acetyl group; A. salmonicida, Aeromonas salmonicida; ASFV, African swine fever virus; B. bronchiseptica, Bordetella bronchiseptica; ChlaDub1, Chlamydia deubiquitylase and deneddylase; CPXV, cowpox virus; CRL, cullin-RING ubiquitin ligase; C. trachomatis, Chlamydia trachomatis; EBV, Epstein–Barr virus; EHEC, enterohaemorrhagic Escherichia coli; EPEC, enteropathogenic E. coli; HAdV-12, human adenovirus 12; HaV, hantaan virus; HCMV, human cytomegalovirus; HCV, hepatitis C virus; HSV, herpes simplex virus; IκBα, NF-κB inhibitor-α (also known as NF-κBIα); IKK, IκB kinase; IRAK, IL-1R-associated kinase; M, membrane protein; MOCV, molluscum contagiosum virus; MYD88, myeloid differentiation primary response protein 88; MYXV, myxoma virus; N, nucleocapsid protein; NEMO, NF-κB essential modulator (also known as IKKγ); PPV, parapoxvirus; RIP1, receptor-interacting protein 1 (also known as RIPK1); RPS3, 40S ribosomal protein S3; RV, rotavirus; SARS-CoV, SARS coronavirus; S. boydii, Shigella boydii; SCF^βTRCP, SKP1, cullin 1 and F-box protein βTRCP; S. flexneri, Shigella flexneri; S. Typhimurium, Salmonella enterica subsp. enterica serovar Typhimurium; TAK1, TGFβ-activated kinase 1; TLR, Toll-like receptor; TNFR, TNF receptor; TRAF, TNFR-associated factor; Ub, ubiquitin; VACV, vaccinia virus; VARV, variola virus; V. parahaemolyticus, Vibrio parahaemolyticus.