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Modulation of Innate Immune Signaling by a Coxiella Burnetii Eukaryotic-Like Effector Protein

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Modulation of Innate Immune Signaling by a Coxiella Burnetii Eukaryotic-Like Effector Protein Modulation of innate immune signaling by a Coxiella burnetii eukaryotic-like effector protein Melanie Burettea,1, Julie Allomberta,1, Karine Lamboua, Ghizlane Maarifia, Sébastien Nisolea, Elizabeth Di Russo Caseb, Fabien P. Blancheta, Cedric Hassen-Khodjac, Stéphanie Cabantousd, James Samuelb, Eric Martineza, and Matteo Bonazzia,2 aInstitut de Recherche en Infectiologie de Montpellier (IRIM) UMR 9004, CNRS, Université de Montpellier, 34293 Montpellier, France; bDepartment of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center College of Medicine, Bryan, TX 77807–3260; cMontpellier Ressources Imagerie (MRI), BioCampus Montpellier, CNRS, INSERM, Université de Montpellier, 34293 Montpellier, France; and dCentre de Recherche en Cancérologie de Toulouse, INSERM, Université Paul Sabatier-Toulouse III, CNRS, 31037 Toulouse, France Edited by Ralph R. Isberg, Tufts University School of Medicine, Boston, MA, and approved April 21, 2020 (received for review August 27, 2019) The Q fever agent Coxiella burnetii uses a defect in organelle There, Ran GTPase activating protein (RanGAP) generates trafficking/intracellular multiplication (Dot/Icm) type 4b secretion Ran-GDP, which dissociates from importin complexes (3). system (T4SS) to silence the host innate immune response during Given its pivotal role in the antimicrobial response, it is not sur- infection. By investigating C. burnetii effector proteins containing prising to observe that a considerable number of bacterial pathogens eukaryotic-like domains, here we identify NopA (nucleolar protein deploy effector proteins that modulate the NF-κB signaling pathway A), which displays four regulator of chromosome condensation (1, 2). These are mostly involved in phosphorylation, ubiquitination, (RCC) repeats, homologous to those found in the eukaryotic Ras- and proteasomal degradation of components of the NF-κB complex, κ related nuclear protein (Ran) guanine nucleotide exchange factor whereas others modulate NF- B-mediated transcription (1, 2). In- (GEF) RCC1. Accordingly, NopA is found associated with the chro- terestingly, it has recently been reported that Salmonella and Orientia matin nuclear fraction of cells and uses the RCC-like domain to tsutsugamushi effector proteins can interfere with nucleocytoplasmic interact with Ran. Interestingly, NopA triggers an accumulation transport, thereby inhibiting nuclear translocation of the p65/RelA transcription factor (4, 5). of Ran-GTP, which accumulates at nucleoli of transfected or in- The Q fever pathogen Coxiella burnetii is an obligate intracellular fected cells, thus perturbing the nuclear import of transcription bacterium that relies on the translocation of effector proteins by a factors of the innate immune signaling pathway. Accordingly, defect in organelle trafficking/intracellular multiplication (Dot/Icm) type qRT-PCR analysis on a panel of cytokines shows that cells exposed 4b secretion system (T4SS) to replicate within large autolysosomal-like C. burnetii nopA dotA to the ::Tn or a Dot/Icm-defective ::Tn mutant compartments inside infected cells (6, 7). Bioinformatics analysis iden- strain present a functional innate immune response, as opposed to tified over 140 C. burnetii genes encoding candidate effector proteins cells exposed to wild-type C. burnetii or the corresponding nopA (7); however, the majority of these remain underinvestigated due to the complemented strain. Thus, NopA is an important regulator of the technical constraints associated with the genetic manipulation of this innate immune response allowing Coxiella to behave as a stealth organism. A subset of effector proteins is involved in the biogenesis of pathogen. Coxiella-containing vacuoles (CCVs), by rerouting membrane traffic to the bacterial replicative niche, while other effectors manipulate the Coxiella burnetii | effector proteins | innate immune sensing | host/ pathogen interactions | nucleocytoplasmic transport Significance he nuclear factor kappa-light-chain-enhancer of activated Coxiella burnetii is a stealth pathogen that evades innate im- TB cells (NF-κB) family of transcription factors regulates the mune recognition by inhibiting the NF-κB signaling pathway. expression of genes associated with diverse cellular functions and This process is mediated by the bacterial Dot/Icm secretion plays a central role in regulating the innate and acquired host system; however, the bacterial effector/s, as well as the mo- immune response to bacterial infections (1, 2). Under physio- lecular mechanism involved in this process have remained un- logical conditions, the transcription factors of the NF-κB family known to date. Here, by investigating C. burnetii proteins with are sequestered in the cytoplasm by specific interactions with eukaryotic-like features (EUGENs), we discovered a new ef- nuclear factor kappa-light polypeptide gene enhancer in B cells fector protein, NopA (nucleolar protein A), which localizes at inhibitor alpha (IκBα), which mask the nuclear localization sig- nucleoli of infected cells and perturbs nucleocytoplasmic nal (NLS) on transcription factors. Exogenous signals, including transport by manipulating the intracellular gradients of the recognition of the tumor necrosis factor (TNF) by TNF receptor GTPase Ran. In doing so, NopA reduces the nuclear levels of or the bacterial lipopolysaccharide (LPS) by toll-like receptor 4 transcription factors involved in the innate immune sensing of (TLR4), activate the NF-κB signaling pathway by triggering the pathogens and single-handedly down-modulates the expres- phosphorylation and proteasomal degradation of IκBα, thus sion of a panel of cytokines. unmasking the NLS on transcription factors. The signal is then recognized by importin-α and members of the importin-β family, Author contributions: M. Burette, J.A., G.M., S.N., E.D.R.C., J.S., E.M., and M. Bonazzi designed research; M. Burette, J.A., K.L., G.M., S.N., E.D.R.C., and E.M. performed re- which mediate the translocation of transcription factors to the search; G.M., S.N., E.D.R.C., F.P.B., C.H.-K., and S.C. contributed new reagents/analytic nucleus through nuclear pore complexes (1). Energy for nuclear tools; M. Burette, J.A., G.M., S.N., E.D.R.C., F.P.B., C.H.-K., J.S., E.M., and M. Bonazzi ana- transport of NLS-containing proteins is provided by intracellular lyzed data; and M. Burette, E.M., and M. Bonazzi wrote the paper. gradients of the small GTPase Ras-related nuclear protein The authors declare no competing interest. (Ran), which interacts with the importin complexes upon nuclear This article is a PNAS Direct Submission. import. GDP-bound Ran is largely cytoplasmic and nuclear Published under the PNAS license. translocation triggers the conversion to the GTP-bound form by 1M. Burette and J.A. contributed equally to this work. means of the Ran guanine nucleotide exchange factor (GEF) 2To whom correspondence may be addressed. Email: [email protected]. RCC-1 (regulator of chromosome condensation-1). In its GTP- This article contains supporting information online at https://www.pnas.org/lookup/suppl/ bound form, Ran triggers the dissociation of importins from the doi:10.1073/pnas.1914892117/-/DCSupplemental. cargo and importin complexes recycle back to the cytoplasm. First published June 1, 2020. 13708–13718 | PNAS | June 16, 2020 | vol. 117 | no. 24 www.pnas.org/cgi/doi/10.1073/pnas.1914892117 Downloaded by guest on September 28, 2021 apoptotic and inflammatory pathways to ensure intracellular persistence CvpB (CBU0021) (12) were used as negative and positive controls, (6). Importantly, C. burnetii behaves as a stealth pathogen, evading the respectively. CvpB, CBU0295, and CBU1217 were efficiently trans- host innate immune response by down-modulating the NF-κBandthe located from 12 h postinfection, whereas AnkA, F, and G were inflammasome signaling pathways (8, 9). The C. burnetii effector protein translocated from 24 h postinfection (Fig. 1 A and B). Finally, AnkC, IcaA (inhibition of caspase activation A) inhibits NOD-like receptor CBU0175, and CBU1724 were also translocated, albeit less efficiently, family pyrin domain containing 3 (NLRP3)-mediated inflammasome at later time points of infection (Fig. 1 A and B). Plasmids encoding activation induced by caspase-11 (8), whereas the NF-κB signaling translocated effectors were then transformed into the C. burnetii pathway is down-modulated in a Dot/Icm-dependent manner, by per- dotA::Tn strain to validate their Dot/Icm-dependent secretion at 72 h turbing the nuclear translocation of the p65/RelA subunit, without af- postinfection. The expression of 6 chimeric proteins was validated by fecting the overall cellular levels of p65 (9). However, the bacterial Western blot using an anti-β-lactamase antibody (SI Appendix,Fig. effector/s involved in this process remains uncharacterized (9). We have S1B). None of the effector proteins were secreted by the Dot/Icm- previously reported the large-scale phenotypic characterization of the C. defective mutant as expected (Fig. 1A). Next, cbu0072 (ankA), burnetii transposon mutant library, which led to gaining important in- cbu0295, cbu0447 (ankF), cbu0781 (ankG), and cbu1217 were cloned sights into the function of the Dot/Icm secretion system, and which into a pLVX-mCherry vector to tag effector proteins at their highlight an important set of virulence determinants (10–12). Impor- N-terminal domain and their localization was investigated in non- tantly, several genes involved in intracellular replication of C. burnetii infected
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