Bendelstein, M. | bioRxiv Science

bioRxiv2023

TGF-β Ligand Interactions in the Response of Caenorhabditis elegans to Bacterial Pathogens

The Transforming Growth Factor beta (TGF-{beta}) family consists of numerous secreted peptide growth factors that play significant roles in cell function, tissue patterning, and organismal homeostasis, including wound repair and immunity. Typically studied as homodimers, these ligands have the potential to diversify their functions through ligand interactions that are synergistic, cooperative, additive, and/or antagonistic. In the nematode Caenorhabditis elegans, there are only five TGF-{beta} ligands, providing an opportunity to dissect ligand interactions in fewer combinations than in vertebrates. As in vertebrates, these ligands can be divided into bone morphogenetic protein (BMP) and TGF-{beta}/Activin subfamilies that predominantly signal through discrete signaling pathways. The BMP subfamily ligand DBL-1 has been well studied for its role in the innate immune response in C. elegans. Here we show that all five TGF-{beta} ligands play a role in the immune response. We also demonstrate that multiple TGF-{beta} ligands act cooperatively as part of this response. We show that the two BMP-like ligands - DBL-1 and TIG-2 - function independently of each other in the immune response, while TIG-2/BMP and the TGF-{beta}/Activin-like ligand TIG-3 function cooperatively. Structural modeling supports the potential for TIG-2 and TIG-3 to form heterodimers. Finally, we show that canonical DBL-1/BMP receptor and Smad signal transducers function in the response to bacterial pathogens, while components of the DAF-7 TGF-{beta}/Activin signaling pathway do not play a role in survival. These results demonstrate a novel potential for BMP and TGF-{beta}/Activin subfamily ligands to interact, and may provide a mechanism for distinguishing the developmental and homeostatic functions of these ligands from an acute response such as the innate immune response to bacterial pathogens.

physiology↗

bioRxiv2023

BMP signaling in the C. elegans immune response to bacterial pathogen regulates anti-microbial peptide expression through cell non-autonomous activity

Host response to pathogens recruits multiple tissues in part through conserved cell signaling pathways. In C. elegans, the bone morphogenetic protein (BMP) like DBL-1 signaling pathway has a role in the response to infection in addition to other roles in development and post-developmental functions. In the regulation of body size, the DBL-1 pathway acts through cell autonomous signal activation in the epidermis (hypodermis). We have now elucidated the tissues that respond to DBL-1 signaling upon exposure to two bacterial pathogens. The receptors and Smad signal transducers for DBL-1 are expressed in pharyngeal muscle, intestine, and epidermis. We demonstrate that expression of receptor-regulated Smad (R-Smad) gene sma-3 in the pharynx is sufficient to improve the impaired survival phenotype of sma-3 mutants and that expression of sma-3 in the intestine has no effect when exposing worms to bacterial infection of the intestine. We also show that two antimicrobial peptide genes - abf-2 and cnc-2 - are regulated by DBL-1 signaling through R-Smad SMA-3 activity in the pharynx. Finally, we show that pharyngeal pumping activity is reduced in sma-3 mutants and that other pharynx-defective mutants also have reduced survival on a bacterial pathogen. Our results identify the pharynx as a tissue that responds to BMP signaling to coordinate a systemic response to bacterial pathogens. Significance StatementO_LIInnate immunity is the first line of defense against pathogens. Conserved cell signaling pathways are known to be involved in host-pathogen response, but how they coordinate a systemic response is less well understood. C_LIO_LIIn the nematode C. elegans, bone morphogenetic protein (BMP) signaling is required for survival on pathogenic bacteria. Using transgenic strains, the authors identify a major role for a specific organ, the pharynx, in BMP-dependent survival. C_LIO_LIThese findings demonstrate that an organ can serve as a pathogen sensor to trigger multiple modes of response to bacterial pathogens, include a barrier response and regulation of anti-microbial peptide expression. C_LI

physiology↗