Review

Intracellular innate immune surveillance devices in plants and animals

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Science  02 Dec 2016:
Vol. 354, Issue 6316, aaf6395
DOI: 10.1126/science.aaf6395

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Shared logic in diverse immune systems

The innate immune systems of both plants and animals depend on the ability to recognize pathogen-derived molecules and stimulate a defense response. Jones et al. review how that common function is achieved in such diverse kingdoms by similar molecules. The recognition system is built for hair-trigger sensitivity and constructed in a modular manner. Understanding such features could be useful in building new pathways through synthetic biology, whether for broadening disease defenses or constructing new signal-response circuits.

Science, this issue p. 10.1126/science.aaf6395

Structured Abstract

BACKGROUND

Pathogens cause agricultural devastation and huge economic losses. Up to 30% of our crops are lost before or after harvest to pathogens and pests, wasting water and human effort. Diseases and pests are major problems for sustainable agriculture in the face of population growth. Similarly, microbial infection remains a major cause of human mortality and morbidity, responsible for ~25% of deaths worldwide in 2012. We lack vaccines for several major infectious diseases, and antibiotic resistance is an ever- growing concern.

Plant and animal innate immune systems respond to pathogen infection and regulate beneficial interactions with commensal and symbiotic microbes. Plants and animals use intracellular proteins of the nucleotide binding domain (NBD), leucine-rich repeat (NLR) superfamily to detect many kinds of pathogens. Plant and animal NLRs evolved from distinct derivatives of a common ancestral prokaryotic adenosine triphosphatase (ATPase): the NBD shared by APAF-1, plant NLR proteins, and CED-4 (NB-ARC) domain class and that shared by apoptosis inhibitory protein (NAIP), CIITA, HET-E, TP1 (NACHT) domain class, respectively. Animals and fungi can carry both NB-ARC and NACHT domain proteins, but NACHT domain proteins are absent from plants and several animal taxa, such as Drosophila and nematodes. Despite the vast evolutionary distance between plants and animals, we describe trans-kingdom principles of NLR activation. We propose that NLRs evolved for pathogen-sensing in diverse organisms because the flexible protein domain architecture surrounding the NB-ARC and NACHT domains facilitates evolution of “hair trigger” switches, into which a virtually limitless number of microbial detection platforms can be integrated.

ADVANCES

Structural biology is beginning to shed light on pre- and postactivation NLR architectures. Various detection and activation platforms have evolved in both plant and animal NLR surveillance systems. This spectrum ranges from direct NLR activation, through binding of microbial ligands, to indirect NLR activation after the modification of host cellular targets, or decoys of those targets, by microbial virulence factors. Homo- and heterotypic dimerization and oligomerization of NLRs add complexity to signaling responses and can enable signal amplification. NLR population genomics across the plant and animal kingdoms is increasing owing to application of new capture-based sequencing methods. A more complete catalog of NLR repertoires within and across species will provide an enhanced toolbox for exploiting NLRs to develop therapeutic interventions.

OUTLOOK

Despite breakthroughs in our molecular understanding of NLR activation, many important questions remain. Biochemical mechanisms of NLR activation remain obscure. Events downstream of plant NLR activation and outputs such as transcription of defense genes, changes in cell permeability, localized cell death, and systemic signaling remain opaque. We do not know whether activated plant NLRs oligomerize or, if they do, how this is achieved, given the diversity of subcellular sites of activation observed for various NLRs. It is not clear whether and how the different N-terminal domains of plant NLRs signal. We have increasing knowledge regarding how animal NLRs assemble and signal, although knowledge gaps remain. Therapeutic interventions in humans targeting NLRs remain on the horizon. Design of novel recognition capabilities and engineering of new or extended NLR functions to counter disease in animals and plants provides tantalizing future goals to address plant and animal health problems worldwide.

NLR tree.

Evolution of NLR genes followed diverging pathways for plant and animal species. Numbers of NLR genes per genome identified computationally range widely, as shown on this stylized evolutionary tree (branches not to scale). The numbers of NLRs can vary markedly even across genomes from closely related taxa. NLRs likely derived from a common ancestor that expressed both NACHT and NB-ARC type NBDs. NACHT is found in animal NLRs, and NB-ARC in plant NLRs. Both occur in fungi. A variety of N- and C-terminal domains have been evolutionarily recruited onto NBDs, including those characteristic of NLRs. The asterisk for tomato indicates that experimental evidence exists to give this precision, as discussed in the main text. The double asterisk for wheat indicates the number of NLRs per diploid genome (wheat is hexaploid). NLR-like fungal proteins lack the LRR domain characteristic of NLRs and are thus not included here.

Abstract

Multicellular eukaryotes coevolve with microbial pathogens, which exert strong selective pressure on the immune systems of their hosts. Plants and animals use intracellular proteins of the nucleotide-binding domain, leucine-rich repeat (NLR) superfamily to detect many types of microbial pathogens. The NLR domain architecture likely evolved independently and convergently in each kingdom, and the molecular mechanisms of pathogen detection by plant and animal NLRs have long been considered to be distinct. However, microbial recognition mechanisms overlap, and it is now possible to discern important key trans-kingdom principles of NLR-dependent immune function. Here, we attempt to articulate these principles. We propose that the NLR architecture has evolved for pathogen-sensing in diverse organisms because of its utility as a tightly folded “hair trigger” device into which a virtually limitless number of microbial detection platforms can be integrated. Recent findings suggest means to rationally design novel recognition capabilities to counter disease.

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