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The Unique Brucella Effectors Nyxa and Nyxb Target SENP3 to Modulate the Subcellular Localisation of Nucleolar Proteins

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The Unique Brucella Effectors Nyxa and Nyxb Target SENP3 to Modulate the Subcellular Localisation of Nucleolar Proteins bioRxiv preprint doi: https://doi.org/10.1101/2021.04.23.441069; this version posted April 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. The unique Brucella effectors NyxA and NyxB target SENP3 to modulate the subcellular localisation of nucleolar proteins Artur Louche1, Amandine Blanco1, Thais Lourdes Santos Lacerda1, Claire Lionnet2, Célia Bergé1, Monica Rolando3, Frédérique Lembo4, Jean-Paul Borg4,5, Carmen Buchrieser3, Masami Nagahama6, Jean-Pierre Gorvel7, Virginie Gueguen-Chaignon8, Laurent Terradot1, , and Suzana P. Salcedo1, 1Laboratory of Molecular Microbiology and Structural Biochemistry, Centre National de la Recherche Scientifique UMR5086, Université de Lyon, Lyon, France 2Laboratoire de Reproduction et Developpement des Plantes, Universite de Lyon, ENS de Lyon, UCBL, INRA, CNRS, Lyon, France 3Institut Pasteur, Biologie des Bactéries Intracellulaires, CNRS UMR 3525, Paris, France 4Aix-Marseille Université, Inserm, Institut Paoli-Calmettes, CNRS, Centre de Recherche en Cancérologie de Marseille (CRCM), Marseille, France 5Institut Universitaire de France 6Laboratory of Molecular and Cellular Biochemistry, Meiji Pharmaceutical University, Tokyo, Japan 7Aix-Marseille Univ, CNRS, INSERM, CIML, Marseille, France 8Protein Science Facility, SFR Biosciences, Centre National de la Recherche Scientifique UAR3444, Université de Lyon, Lyon, France The cell nucleus is a primary target for intracellular bacterial SENP3 functions as a processing enzyme for the SUMO2/3 pathogens to counteract immune responses and hijack host sig- precursor and as a deconjugase of SUMOylated substrates. nalling pathways to cause disease. The mechanisms controlling SENP3 is mostly nucleolar and has been directly implicated nuclear protein localisation in the context of stress responses in- in cellular adaptation to mild oxidative stress (3) and star- duced upon bacterial infection are still poorly understood. Here vation (4). More recently, SENP3 was also proposed as a we show that the Brucella abortus effectors NyxA and NyxB in- negative regulator of autophagy during nutritional stress (4). terfere with the host sentrin specific protease 3 (SENP3), which is essential for intracellular replication. Translocated Nyx ef- Autophagy, is one of the key stress-response mechanisms en- fectors directly interact with SENP3 via a defined acidic patch abling cells to quickly adapt by engulfing cellular compo- identified from the crystal structure of NyxB, preventing its nu- nents such as damaged organelles (e.g. mitophagy and ER- cleolar localisation at the late stages of the infection. By se- phagy), toxic protein aggregates (proteophagy) or microbes questering SENP3, the Nyx effectors induce the cytoplasmic ac- (xenophagy) and directing them for degradation. Ribophagy cumulation of the nucleolar AAA-ATPase NVL, the large sub- is a selective type of autophagy involved in the degradation unit ribosomal protein L5 (RPL5) and the ribophagy receptor of ribosomes that disrupts ribosomal biogenesis and provides NUFIP1 in Nyx-enriched structures in the vicinity of replicat- a swift source of nutrients for cells (5-7). Although multi- ing bacteria. This shuttling of ribosomal biogenesis-associated ple ribophagy pathways have been characterized depending nucleolar proteins is negatively regulated by SENP3 and de- on the specific stress signals involved, ribophagy was shown pendent on the autophagy-initiation protein Beclin1, indicative of a ribophagy-derived process induced during Brucella infec- to be dependent on the autophagy-initiation protein Beclin1 tion. Our results highlight a new nucleomodulatory function by (7). A single ribophagy receptor has been described to date two unique Brucella effectors, and reveal that SENP3 is a crit- (8), the nuclear fragile X mental retardation-interacting pro- ical regulator of the subcellular localisation of multiple nucleo- tein (NUFIP1), a nucleoplasmic protein first shown to be in- lar proteins during Brucella infection, promoting intracellular volved in 60S rRNA biogenesis in yeast (9). NUFIP1 is ex- replication. ported to the host cytoplasm in human cells upon starvation or mTOR inhibition, where it binds ribosomes and mediates Brucella | SENP3 | nucleomodulation | nuclear stress| effectors Correspondence: [email protected] and [email protected] their degradation (8). NUFIP1 is necessary for maintaining nucleoside/nucleotide levels and cell survival in the context of prolonged nutrient deprivation (8). Introduction Bacterial pathogens can escape autophagy-mediated killing The spatial organization of eukaryotic cells and accurate sub- and, in some cases, modulate autophagy components and cellular targeting of macromolecules is absolutely essential pathways to promote virulence. One such example is Bru- for the regulation of numerous cellular processes, namely cell cella abortus, an intracellular pathogen that extensively repli- growth, survival and stress responses. Indeed, mislocalisa- cates inside cells in a vacuole derived from the endoplasmic tion of proteins in the cell has been associated with cellular reticulum (ER), known as replicative Brucella-containing stress and multiple diseases (1). The nucleus plays a critical vacuole (rBCV). Although the role of autophagy in Brucella role in sensing and orchestrating the overall host responses virulence remains poorly understood, several proteins have to stress. Several nuclear proteins have been shown to act as been implicated in different stages of the intracellular life cy- important stress-sensors in the cell, including the sentrin spe- cle, notably the formation of rBCVs (Atg9 and WIPI-1) (10) cific protease 3 (SENP3) which is also involved in regulation and induction of autophagic BCVs mediating bacterial egress of cell cycle, survival pathways and ribosomal biogenesis (2). from infected cells (ULK and Beclin1) (11). The establish- Louche et al. | bioRχiv | April 23, 2021 | 1–19 bioRxiv preprint doi: https://doi.org/10.1101/2021.04.23.441069; this version posted April 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. ment of its replication niche requires the VirB/D type 4 se- ysis identified another gene, BAB1_1101 (BAB_RS21200), cretion system (T4SS) that translocates effector proteins into encoding for a protein with 82% identity to NyxA, but with- host cells that specifically modulate cellular functions. Only out a carboxy-terminal CAAX motif (Supplementary Figure very few Brucella effectors have been characterized to date, 1A). For consistency, we have named it NyxB and found that including some targeting innate immune responses (12-14) it was also translocated by B. abortus into host cells, albeit and the secretory pathway (15). to lower levels than NyxA at both 4 and 24h post-infection In this study we identify two new translocated effectors, (Figure 1A and B and Supplementary Figure 1B). Both NyxA NyxA and NyxB, that interact with the SENP3, leading to and NyxB are well conserved within the Brucella species and its subnuclear mislocalisation during infection. The crystal show little homology to other bacterial proteins. Paralogs of structure of NyxB and structure-based mutagenesis enabled NyxA and B are present in members of the closely related us to pinpoint residues of the protein essential for SENP3 genus Ochrobactrum from the Brucellaceae family. interaction. We show that NyxA and NyxB mediate the for- To gain insight into the mechanism of translocation of NyxA mation of Brucella-induced foci enriched in both effectors, and NyxB, we infected cells for 4h, a time point that en- the 60S ribosomal subunit protein RPL5, the AAA-ATPase ables a comparison between the wild-type and the DvirB9 NVL, and the ribophagy receptor NUFIP1. The formation mutant strain lacking a functional T4SS. NyxA translocation of these structures is dependent on Beclin1 and is negatively was significantly reduced in a virB mutant strain, suggesting regulated by SENP3, that Brucella sequesters to sustain in- dependency on the T4SS. We should note that a small num- tracellular replication. The modulation of nuclear functions ber of cells infected with the DvirB9 expressing NyxA were during infection is an important virulence strategy shared by positive for CCF2 compared to BAB1_0466, for which no a growing number of bacterial pathogens (16). In most cases, translocation was detected suggesting a proportion of NyxA this nuclear targeting results in a fine regulation of host gene could also be translocated independently of the T4SS (Sup- expression or control of cell cycle to benefit host coloniza- plementary Figure 1B and C). Curiously, the translocation of tion and persistence. In this study we highlight a new nu- NyxB was independent of the T4SS (Supplementary Figure cleomodulation mechanism that promotes perturbation of the 1B). subcellular localisation of nucleolar proteins during bacterial To confirm that NyxA was indeed translocated across the vac- infection. uolar membrane during infection, we constructed new strains with NyxA fused on its N-terminus with a 4HA epitope tag, Results successfully used for imaging bacterial effectors (23). We then infected HeLa cells, a well-characterised
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