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Self-Identity Barcodes Encoded by Six Expansive Polymorphic Toxin Families Discriminate Kin in Myxobacteria

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Self-Identity Barcodes Encoded by Six Expansive Polymorphic Toxin Families Discriminate Kin in Myxobacteria Self-identity barcodes encoded by six expansive polymorphic toxin families discriminate kin in myxobacteria Christopher N. Vassalloa,1 and Daniel Walla,2 aDepartment of Molecular Biology, University of Wyoming, Laramie, WY 82071 Edited by Christine Jacobs-Wagner, Yale University, West Haven, CT, and approved October 24, 2019 (received for review July 20, 2019) Myxobacteria are an example of how single-cell individuals can dynamic OM proteins, and, when 2 compatible cells touch, transition into multicellular life by an aggregation strategy. For these multiple receptor complexes from each cell coalesce into distinct and all organisms that consist of social groups of cells, discrimination foci that bridge the boundary between the 2 cells. This transient against, and exclusion of, nonself is critical. In myxobacteria, TraA is interaction culminates in an apparent membrane fusion and bi- a polymorphic cell surface receptor that identifies kin by homotypic directional transfer of proteins and lipids before cells separate by binding, and in so doing exchanges outer membrane (OM) proteins gliding motility (5–7). This striking and robust behavior is and lipids between cells with compatible receptors. However, TraA thought to help rejuvenate and maintain homeostasis of the cell variability alone is not sufficient to discriminate against all cells, as envelope in a population that ages or encounters insults in traA allele diversity is not necessarily high among local strains. To constantly fluctuating environments (8, 9). increase discrimination ability, myxobacteria include polymorphic In nutrient-rich soils, myxobacteria populations are numerous OM lipoprotein toxins called SitA in their delivered cargo, which and diverse (10, 11). Local strains compete with each other and poison recipient cells that lack the cognate, allele-specific SitI immu- must establish and maintain a group identity by recognizing and nity protein. We previously characterized 3 SitAI toxin/immunity cooperating with kin while excluding nonkin. TraA serves as one pairs that belong to 2 families. Here, we discover 4 additional SitA self-recognition determinant by binding to cells with matching families. Each family is unique in sequence, but share the character- receptors (2, 12). Sequence polymorphisms within the TraA istic features of SitA: OM-associated toxins delivered by TraA. We MICROBIOLOGY variable domain, which determines recognition specificity, is high, demonstrate that, within a SitA family, C-terminal nuclease domains are polymorphic and often modular. Remarkably, sitA loci are strik- and prior studies with a limited allele set experimentally de- > termined or predicted >60 distinct TraA recognition groups (3). ingly numerous and diverse, with most genomes possessing 30 and Myxococcus up to 83 distinct sitAI loci. Interestingly, all SitA protein families are However, analysis of TraA allele variation between xanthus serially transferred between cells, allowing a SitA inhibitor cell to strains that are colocalized in the soil revealed that some poison multiple targets, including cells that never made direct con- divergent strains are in fact compatible for OME (2, 13). In other tact. The expansive suites of sitAI loci thus serve as identify barcodes words, TraA is not always sufficient to discriminate between clonal to exquisitely discriminate against nonself to ensure populations are cells and competitors. This suggests that myxobacteria have ad- genetically homogenous to conduct cooperative behaviors. ditional mechanisms to identify clonemates. Indeed, to increase kin recognition | polymorphic toxins | outer membrane exchange | Significance myxobacteria Social organisms that share resources must identify their kin ulticellular organisms or groups of social cells need to to avoid exploitation by nonself competitors; however, un- Midentify clonal cells to coordinate specific behaviors and derlying mechanisms to explain discrimination are lacking. allow resources to be directed toward them. Central to under- Myxobacteria, which aggregate into tissue-like groups, use a standing these fundamental processes is identifying the proteins 2-step self-identification mechanism in which cells interact by a involved in self/nonself-recognition and the mechanisms indi- highly variable cell surface receptor that catalyzes cellular viduals use to discriminate against nonkin to form cohesive and cargo exchange. This cargo includes polymorphic toxins that harmonious populations. Myxobacteria represent tractable model poison nonclonal cells, which lack specific immunity genes. systems to study how kin recognition evolves and functions at a Here, we identified 6 unique families of toxins that are strik- molecular level. Myxobacterial cells typically live in social groups ingly numerous in myxobacterial genomes. Together, arrays of in the soil, where they move and feed on prey microbes. When toxins form what we describe as self-identity barcodes that nutrients are depleted, they undergo a synchronized, cooperative exquisitely distinguish clonal cooperators from nonself. This work highlights how selfish and discriminating genes, which developmental program culminating in the formation of a multi- expand in vast combinations in bacterial genomes, help to di- cellular fruiting body that harbors dormant spores. Cooperating versify and insulate social groups. with kin cells while excluding incompatible individuals is impera- tive for them to maintain a viable social network. During vege- Author contributions: C.N.V. and D.W. designed research; C.N.V. performed research; tative growth, cells maintain close contacts as they move past one C.N.V. analyzed data; and C.N.V. and D.W. wrote the paper. another by gliding motility. Upon each physical contact, cells The authors declare no competing interest. monitor the identity of their neighbors by homotypic interactions This article is a PNAS Direct Submission. of a highly polymorphic cell surface receptor called TraA, along Published under the PNAS license. – with its partner protein TraB (1 3). When neighboring cells have 1Present address: Department of Biology, Massachusetts Institute of Technology, Cambridge, identical or matching TraA receptors, they exchange large MA 02142. amounts of cell envelope material in a process called outer 2To whom correspondence may be addressed. Email: [email protected]. membrane exchange (OME). OME can be directly visualized This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. microscopically by rapid and efficient cell-to-cell transfer of 1073/pnas.1912556116/-/DCSupplemental. outer-membrane (OM) fluorescent reporters (4, 5). TraA/B are www.pnas.org/cgi/doi/10.1073/pnas.1912556116 PNAS Latest Articles | 1of11 Downloaded by guest on September 24, 2021 specificity of OME beyond TraA–TraA interactions, there is a modules that share no sequence similarity. The escort domains are second authentication or discrimination step. OM-localized poly- thought to facilitate CT toxin delivery into the cytoplasm following morphic toxins are included among the wide array of cell envelope delivery to the OM of the target cell. sitA3 is similar to the sitA1/2 cargo that is delivered during OME (14). genes in that it encodes a lipoprotein toxin delivered by OME, Polymorphic toxin/immunity pairs are ubiquitous in microbial contains a modular CT toxin domain, and is associated with a genomes and provide a means to exclude nonkin from clonal downstream sitI3 immunity gene. Interestingly, however, SitA3 populations (1, 15). Toxins typically consist of a domain that shares no sequence homology with SitA1 and SitA2. Each of the 3 facilitates delivery of a C-terminal (CT) toxin domain, which sitA loci have an overlapping homologous upstream open reading causes growth inhibition or death of a susceptible cell that re- frame (ORF) called sitB, whose gene product enhances the ability ceives it. Immunity genes, almost always encoded next to the of SitA to kill target cells, but is not essential for SitA function toxin, provide allele-specific protection from the toxic activity. (14). SitB contains a signal sequence, and is predicted to form a These systems can diversify by amino acid changes in residues β-barrel in the OM, but has no clear homology to any character- involved in the molecular recognition between the toxin and the ized domains. Since SitA1/2 and SitA3 are not homologous, it immunity proteins, resulting in polymorphisms and the forma- raises the possibility that there are other SitA proteins that share tion of new toxin/immunity specificity pairs (16). As microbial similar function and delivery mechanism but do not necessarily strains diversify, so too do their toxin repertoires, and horizontal share sequence homology. Here, we describe the discovery and gene transfer (HGT) plays a major role in toxin/immunity dis- characterization of 4 additional families of SitAI that belong to the semination and diversification between populations (15, 17, 18). overarching SitA class of proteins. We demonstrate that SitAI4, Further, toxins involved in interstrain warfare often have a SitAI5, SitAI6, and SitAI7 are OME-dependent toxin families that modular architecture in that diverse toxin domains are found at are strikingly numerous and diverse within myxobacterial genomes the C terminus of a particular delivery domain and appear to be predicted to contain functional TraAB proteins. Remarkably, mixed and matched by recombination between various delivery some myxobacterial genomes contain
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