BACKGROUND Diverse organisms, from archaea and bacteria to plants and humans, use receptor systems to recognize both pathogens and dangerous self-derived or environmentally derived stimuli. These intricate, well-coordinated immune systems, composed of innate and adaptive components, ensure host survival. In the late 20th century, researchers identified the Toll/interleukin-1/resistance gene (TIR) domain as an evolutionarily conserved component of animal and plant innate immune systems. Today, TIR-domain proteins are known to be broadly distributed across the tree of life. The TIR domain was first recognized as an adaptor for the assembly of macromolecular signaling complexes in mammalian innate immune pathways. Work on axon degeneration in animals—as well as on plant, archaeal, and bacterial immune systems—has uncovered additional enzymatic activities for TIR domains. ADVANCES Mammalian axons initiate a self-destruct program upon injury and during disease that is mediated by the sterile alpha and TIR motif containing 1 (SARM1) protein. The SARM1 TIR domain enzymatically consumes the essential metabolic cofactor nicotinamide adenine dinucleotide (NAD + ) to promote axonal death. Identification of the SARM1 NAD + -consuming enzyme (NADase) revealed that TIR domains can function as enzymes. Given the evolutionary conservation of TIR domains, studies investigated whether the SARM1 TIR NADase was also conserved. Indeed, bacteria, archaea, and plant TIR domains possess NADase activity. In prokaryotes, TIR NADase activity is found in an ancient antiphage immune system. In plants, identification of TIR NADase activity and linkage of TIR enzymatic products to downstream signaling components addressed the question of how nucleotide-binding, leucine-rich repeat (NLR) receptors trigger hypersensitive cell death during an immune response. Studies in plants show that their TIR domains can cleave nucleic acids and possess 2′,3′ cyclic adenosine monophosphate (2′,3′-cAMP) and 2′,3′ cyclic guanosine monophosphate (2′,3′-cGMP) synthetase activity that aids cell death programs in plant innate immunity. Thus, TIR domains constitute an ancient family of enzymes that are activated in immune and cell death pathways. OUTLOOK The discovery of TIR-domain enzyme activities carries implications for innate immunity and neurodegeneration. The identification of the SARM1 NADase defined a drug target for a wide number of neurodegenerative diseases that is being exploited in both preclinical and clinical studies. Hyperactive mutations in the SARM1 NADase have been discovered in amyotrophic lateral sclerosis (ALS) patients. Future work will seek to clarify the contribution of the SARM1 axon degeneration pathway to ALS pathogenesis. NAD + biology influences cellular processes from metabolism to DNA repair to aging. How TIR enzymes influence the NAD + metabolome and its associated pathways in bacteria, archaea, plants, and animals will be an exciting area for upcoming investigation. The discovery of the diversity of TIR enzymatic products is revealing signaling pathways across kingdoms. Discovery of TIR enzymatic function in plants and animals may yet inspire studies of enzymatic functions for Toll-like receptors in animals. We anticipate that cross-kingdom studies of TIR-domain function will guide interventions that will span the tree of life, from treating human neurodegenerative disorders and bacterial infections to preventing plant diseases. Conserved TIR-domain enzymatic activity. TIR-domain proteins from prokaryotes and eukaryotes cleave NAD + into nicotinamide (Nam), ADP-ribose (ADPR), cyclic ADP-ribose (cADPR), isomers of cyclic ADP-ribose (2′ or 3′cADPR), and related molecules [e.g., phosphoribosyl adenosine monophosphate (pRib-AMP)]. Plant TIR domains also possess a nuclease activity, can degrade DNA and RNA, and can function as a 2′,3′-cAMP or 2′,3′-cGMP synthetase. TIR enzymatic activity drives cell death and immune pathways across kingdoms. TIR activity can kill cells directly through NAD + depletion or indirectly using enzymatic products as signal molecules. The representative TIR domain structure shown here is Protein Data Bank ID 6O0Q. EDS1, enhanced disease susceptibility 1; ThsA, Thoeris A.
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Convergent Loss of an EDS1/PAD4 Signaling Pathway in Several Plant Lineages Reveals Coevolved Components of Plant Immunity and Drought Response
Plant innate immunity relies on nucleotide binding leucine-rich repeat receptors (NLRs) that recognize pathogen-derived molecules and activate downstream signaling pathways. We analyzed the variation in NLR gene copy number and identified plants with a low number of NLR genes relative to sister species. We specifically focused on four plants from two distinct lineages, one monocot lineage (Alismatales) and one eudicot lineage (Lentibulariaceae). In these lineages, the loss of NLR genes coincides with loss of the well-known downstream immune signaling complex ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1)/PHYTOALEXIN DEFICIENT 4 (PAD4). We expanded our analysis across whole proteomes and found that other characterized immune genes were absent only in Lentibulariaceae and Alismatales. Additionally, we identified genes of unknown function that were convergently lost together with EDS1/PAD4 in five plant species. Gene expression analyses in Arabidopsis (Arabidopsis thaliana) and Oryza sativa revealed that several homologs of the candidates are differentially expressed during pathogen infection, drought, and abscisic acid treatment. Our analysis provides evolutionary evidence for the rewiring of plant immunity in some plant lineages, as well as the coevolution of the EDS1/PAD4 pathway and drought responses.
more » « less- Award ID(s):
- 1701918
- NSF-PAR ID:
- 10151243
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- The Plant Cell
- Volume:
- 32
- Issue:
- 7
- ISSN:
- 1040-4651
- Page Range / eLocation ID:
- p. 2158-2177
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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The loss‐of‐function of
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