Pathogens use an array of molecules, termed effectors, to successfully colonize hosts (Win et al., 2012). Intracellular detection of effectors relies on immune receptors from the nucleotide-binding, leucine-rich repeats (NLR) superfamily (Bentham et al., 2020; Jones et al., 2016; Saur et al., 2021). Upon recognition, NLRs act as nucleotide-operated switches, exchanging ADP for ATP (Bernoux et al., 2016; Tameling et al., 2002; Wang et al., 2019b; Williams et al., 2011), and oligomerize into supramolecular signalling platforms (Hu et al., 2015; Ma et al., 2020; Martin et al., 2020; Sharif et al., 2019; Tenthorey et al., 2017; Wang et al., 2019a; Zhang et al., 2015). This leads to immune responses, including programmed cell death, that restrict pathogen growth. The assembly of such sophisticated molecular machinery needs to be well coordinated and tightly regulated to ensure an efficient immune response, while avoiding the deleterious effect of constitutive immune activation (Chae et al., 2016; Karasov et al., 2017; Li et al., 2020; Richard and Takken, 2017).

NLRs form the most expanded and diversified protein family in plants (Meyers et al., 2003; Van de Weyer et al., 2019; Yue et al., 2012). Since their discovery, plant NLRs have been heavily studied and around 450 NLR proteins from 31 genera of flowering plants have been functionally validated (Kourelis et al., 2021). Plant NLRs present multiple layers of complexity (Barragan and Weigel, 2021), often functioning in genetically linked pairs (Eitas and Dangl, 2010; Griebel et al., 2014) or as part of complex immune networks (Wu et al., 2018). In such cases, NLRs specialize their role in immune activation, acting as ‘sensors’ that detect pathogen effectors or as ‘helpers’ that amplify and propagate immune signalling (Adachi et al., 2019b; Jubic et al., 2019). Paired NLRs are prevalent in plant genomes (Stein et al., 2018; Wang et al., 2019c) with a subset of sensor NLRs harbouring atypical domains integrated into their architecture (Bailey et al., 2018; Kourelis et al., 2021; Kroj et al., 2016; Sarris et al., 2016). These domains can be derived from pathogen host targets that act as sensor domains within NLRs by binding pathogen effectors (Białas et al., 2018; Cesari et al., 2014; Maidment et al., 2021; Oikawa et al., 2020).

Cooperating NLRs must balance a trade-off between adaptive evolution to fast-evolving pathogens and maintaining a fine-tuned regulation of complex receptor assemblies. NLRs with different evolutionary trajectories may drift apart and eventually mismatch. When these mismatched NLRs are combined in the same individual through genetic crossing, constitutive immune activation can occur, leading to deleterious phenotypes including dwarfism, necrosis, and lethality (Bomblies et al., 2007; Chae et al., 2014). These ‘Dangerous Mix’ phenotypes are known in plant breeding as hybrid necrosis and have important implications in agriculture (Caldwell and Compton, 1943; Calvo-Baltanás et al., 2020; Hermsen, 1963b; Hermsen, 1963a; Li and Weigel, 2021; Wan et al., 2021; Yamamoto et al., 2010). In Arabidopsis, two genetically unlinked NLR proteins encoded on different chromosomes were shown to physically associate in the mixed immune background of hybrid plants, underpinning hybrid necrosis (Tran et al., 2017). Similarly, association between NLRs and alleles of non-NLR proteins derived from a different genetic background was also shown to induce NLR activation and autoimmune phenotypes (Barragan et al., 2019; Li et al., 2020). However, the biochemical basis of adaptive specialization in genetically linked NLR receptor pairs remains largely unknown. In particular, we know little about how coevolution between paired NLRs has impacted their activities. We lack a validated framework to explain how plant immune receptors adapt and specialize, even though this process has important consequences for plant diversification and evolution (Bomblies and Weigel, 2007; Calvo-Baltanás et al., 2020; Dobzhansky, 1937; Li and Weigel, 2021).

The rice NLRs Pik-1 and Pik-2 form a linked gene pair arranged in an inverted configuration on chromosome 11 with only ~2.5 kb separating their start codons (Ashikawa et al., 2008). The Pik pair is present in the genetic pool of rice cultivars as two major haplotypes (Białas et al., 2021; Kanzaki et al., 2012). Pik pairs belonging to the K haplotype confer resistance to strains of the rice blast fungus, Magnaporthe oryzae, that harbour the effector AVR-Pik (Ashikawa et al., 2008). The sensor NLR Pik-1 binds AVR-Pik effectors through a heavy metal-associated (HMA) domain integrated into its architecture (De la Concepcion et al., 2018; Kanzaki et al., 2012; Maqbool et al., 2015). Upon effector recognition, Pik-1 cooperates with the helper NLR Pik-2 to activate immune signalling (Zdrzałek et al., 2020) that leads to pathogen resistance. The Pik NLR pair occurs as allelic series in both Japonica and Indica rice cultivars (Chaipanya et al., 2017; Costanzo and Jia, 2010; Hua et al., 2012; Xu et al., 2008). The AVR-Pik effectors are also polymorphic and present signatures of selection (Bentham et al., 2021; Białas et al., 2018; Yoshida et al., 2009). Allelic Pik NLRs have differential recognition specificities for the AVR-Pik variants (De la Concepcion et al., 2021; Kanzaki et al., 2012), which is underpinned by differential effector binding to the Pik-1 HMA domain (De la Concepcion et al., 2018; De la Concepcion et al., 2021; Maqbool et al., 2015). Two allelic variants of Pik-1, Pikp-1 and Pikm-1, acquired high-affinity binding to the M. oryzae AVR-Pik effector through convergent evolution of their HMA domains (Białas et al., 2021). Additionally, Pikm-1 and Pikh-1 alleles have been shown to convergently evolve towards extended recognition specificity of AVR-Pik variants (De la Concepcion et al., 2021). This adaptive evolution towards recognition of rapidly evolving effectors has led to marked diversification of the integrated HMA domain (Białas et al., 2021). As a consequence, Pik-1 HMA domain is the most sequence-diverged domain in the Pik NLR pair (Białas et al., 2021; Białas et al., 2018; Costanzo and Jia, 2010).

While Pik-1 acts as a sensor, Pik-2 acts as a helper NLR that is required for the activation of immune responses (Maqbool et al., 2015; Zdrzałek et al., 2020). Evolutionary analyses have shown that the genetic linkage of this NLR pair is ancient and revealed marked signatures of adaptive evolution in the integrated HMA domain of Pik-1 (Białas et al., 2021). However, little is known about sensor/helper coevolution in Pik and how these multidomain proteins have adapted to changes in the rapidly evolving integrated HMA domain of Pik-1.

Here, we used two allelic variants of Pik, Pikp and Pikm, to explore NLR sensor/helper specificity (Figure 1—figure supplement 1). We challenged the hypothesis that throughout evolutionary time these two allelic Pik pairs have become diverged to the level of incompatibility. Indeed, mismatched pairs of Pik-1 and Pik-2 display constitutive cell death when combined in the heterologous system Nicotiana benthamiana, which is reminiscent of autoimmune phenotypes. We identified a single amino acid polymorphism in the helper NLR Pik-2 that underpins both allelic specialization and immune homeostasis. This finding allowed to reconstruct the evolutionary history of this coevolution. Altogether, these results demonstrate that NLR pairs can undergo co-adaptation and functional specialization, offering a molecular framework to understand how they evolve to respond to pathogen effectors while maintaining a tight regulation of immune responses.

The work presented here highlights sensor/helper coevolution in an allelic rice NLR pair and the basis of their functional diversification towards differential effector recognition specificities (Figure 12). We discovered that a single amino acid polymorphism underpins specialization of the helper Pik-2 NLR to its corresponding Pik-1 sensor NLR. Changes in this residue affect cell death outcomes in effector recognition and autoimmune phenotypes. By narrowing down the contribution of NLR specialization to a single amino acid, we could trace the evolutionary history of this polymorphism (Figure 12).

Figure 12

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The notion that NLRs can work together in pairs is now well established in the field of plant–microbe interactions (Adachi et al., 2019b; Jubic et al., 2019). Under this emerging framework, it is predicted that cooperating NLRs co-adapt to optimize and maintain a tight control over immune responses. However, the extent to which paired NLRs coevolve to efficiently respond to pathogen effectors while keeping a fine-tuned regulation of immune responses is not well understood at the molecular level. Particularly intriguing is how rapid changes driven by coevolution with pathogen effectors and major evolutionary events, such as the integration of an unconventional domain, impact NLR co-adaptation.

The genetic linkage of the Pik NLR pair has been maintained in grass genomes for tens of millions of years and emerged before the integration of the HMA domain in Pik-1 (Białas et al., 2021). This suggests that Pik-1 and Pik-2 have been coevolving for a long time, potentially before providing resistance to the blast fungus. Thus, the integration of the HMA domain in Pik-1, and its subsequent rapid coevolution with rice blast effectors, may have represented a major perturbation on the coevolutionary equilibrium in the paired Pik NLRs. Here, we demonstrated how allelic Pik NLR pairs have differentially coevolved and functionally specialized, leading to autoimmune phenotypes when mismatched. This suggests that in response to HMA integration and diversification in the sensor NLR Pik-1, its helper NLR Pik-2 has acquired polymorphisms to avoid loss of function and/or triggering autoimmunity.

Here, we used Pikp and Pikm as representative examples of the two clades in which Pik alleles are distributed (Białas et al., 2021; De la Concepcion et al., 2021). Given the similarity between sensor and the helper NLRs within each clade, we predict the phenotypes reported will extend to other similar mismatches between Pik alleles.

To date, integrated domains have been primarily found in paired NLRs that are located in co-regulatory modules with a shared promoter region (Cesari et al., 2014). Therefore, the spatial regulation of NLRs with unconventional domains in pairs might be a general mechanism to mitigate NLR misregulation as a consequence of domain integrations or their accelerated evolutionary rates compared with other NLR domains (Białas et al., 2021).

We have used N. benthamiana as a heterologous system to investigate cell death and autoimmunity in the Pik NLRs. Cell death responses mediated by Pik in this system have previously been shown to correlate with immune responses in rice (De la Concepcion et al., 2018; De la Concepcion et al., 2021; Maqbool et al., 2015). Additional experiments in rice could further clarify the extent to which Pik mismatching leads to autoimmunity and hybrid necrosis. However, given that Pik alleles localize in the same genomic region in different cultivars, and the tight linkage between sensor and helper NLRs (head-to-head orientation with ~3000 bp shared promoter; Ashikawa et al., 2008), obtaining rice plants with mismatched combinations of sensor and helper by conventional breeding would be challenging.

Pik autoimmunity also poses the question of whether mismatching between alleles could impose a reproductive barrier. However, to our knowledge, no rice cultivar with mixed Pik alleles has been reported to date (Figure 6A). Different allele pairs are present (probably introgressed) in both Japonica and Indica rice varieties. Again, this may be due to difficulties of mixing sensor and helper NLRs in the context of spatial regulation and the tightly genetic linkage.

We found that mismatched allelic NLR pairs can lead to constitutive cell death. We further narrowed down this phenotype to a single Asp to Glu polymorphism, which is the same polymorphism that underpins an extended cell death response to AVR-Pik effectors. Introducing this Asp230Glu polymorphism in Pikp-2 led to an increase of cell death in response to AVR-Pik effectors as well as to autoimmune phenotypes. As these amino acids have very similar properties, it is intriguing how a fairly minor difference can underpin such a major phenotype. The mechanistic basis of this autoactivation phenotype remains obscure, but it is possible that the larger amino acid side chain (Glu carries an extra methylene group in the side chain) is sufficient to perturb protein–protein interactions that support transition to the active state of the NLR pair. Analogous Asp to Glu changes have been previously shown to act as a gain-of-function mutation in response regulators and transcription factors (Sakai et al., 2001; To et al., 2007). In some cases, the Asp residue is a target of phosphorylation and the change to Glu partially acts as a phosphomimetic mutation that leads to an active form (Klose et al., 1993). Indeed, phosphorylation plays an important role in the activation of the mammalian NLR NLRP3 and the phosphorylation sites are buried in the structure of the resting state (Hochheiser et al., 2021). However, to date, there is no evidence to suggest that phosphorylation of Asp230 is involved in Pikp-2 activation. The Asp to Glu change did not prevent sensor/helper association, although it affected association preference. Altogether, this illustrates that small changes in NLR receptors can have profound phenotypical effects on immune regulation and cell death responses.

We still lack detailed information about the activation mechanism of paired plant NLRs although a cooperation mechanism has been proposed for the Pik NLR pair (Zdrzałek et al., 2020). By taking advantage of constitutively active Pik sensor/helper combinations and mutants, we can expand our knowledge of NLR signalling mechanisms. The use of constitutively active immune receptors as a research tool is starting to be explored in the field of NLR biology. This approach has the advantage of simplifying the complex requirements of immune activation by removing the variability of the effector. It also renders full receptor activation, whilst relying solely on effector recognition can provide a mixture of active and inactive receptors.

Sensor and helper Pik NLRs form a pre-activation complex (Zdrzałek et al., 2020). Activation of immune responses may rearrange the composition of this complex, possibly affecting sensor/helper stoichiometry, as described for NAIP/NLRC4 inflammasomes (Hu et al., 2015; Tenthorey et al., 2017; Zhang et al., 2015). This rearrangement is dependent on nucleotide binding and has been fine-tuned during the evolutionary process, as depicted in the competition assays in the Pik pair.

Autoactive mutations in Pikp-2 led us to re-evaluate the involvement of conserved P-loop and MHD motif of sensor and helper Pik NLRs in signalling activation. In contrast to the previously described cooperation mechanism of Pik regulation (Białas et al., 2018; Zdrzałek et al., 2020), the P-loop of sensor NLR Pik-1 is important but not necessary for NLR activation. This also deviates from the negative regulation mechanism described for other NLR pairs such as Pia or Arabidopsis RRS1/RPS4 (Césari et al., 2014; Cesari et al., 2013; Le Roux et al., 2015; Sarris et al., 2015) and suggests that the Pik pair may trigger cell death via a different mechanism. Surprisingly, combining Pik-2 mutants in the P-loop and MHD motifs within the autoactive Pikp-1/Pikp-2 Asp230Glu background did not lead to a reduction in constitutive cell death, as observed with the Pikp-2 wild-type (Figure 11). This suggests that these mutants cannot outcompete Pikp-2 Asp230Glu from a complex with Pikp-1, meaning that mutations in these domains, although they do not prevent association, may affect the strength of sensor/helper association. However, the requirements of these regions for the formation of a hypothetical NLR complex remain unclear. Future experiments using autoactive combinations should help unravel the requirements of Pik NLR immune signalling and will reveal the nature of the changes undergone by NLRs during activation.

While Pikp-2 Asp230Glu induces a strong constitutive cell death when paired with Pikp-1, it only leads to a weak cell death response in the absence of the effector when paired with Pikm-1. This may reflect another layer of sensor/helper coevolution where sensor Pikm-1 may have adapted to supress uncontrolled activation triggered by the Asp230Glu polymorphism found in Pikm-2. Given the similarity between Pikp-1 and Pikm-1 outside the integrated HMA (Białas et al., 2021), this domain may harbour the compatibility determinant with this polymorphism. Integrated domains may have regulatory functions other than binding effectors (Ma et al., 2018). Further comparative analysis between Pikp and Pikm HMA domains, using the repertoire of mutants developed here, will be required to address this question that is important for future engineering efforts based on the Pik system.

In summary, this work provides an evolutionary framework for how differential selective pressures, such as recognition of pathogen strains via effector binding, impact NLRs pairs. It uncovers the potential of paired NLRs to give rise to autoimmune phenotypes during evolution and links pathogen perception and autoimmunity.

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Plots and Blots.

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Author details

1. Juan Carlos De la Concepcion

   1. Gregor Mendel Institute of Molecular Plant Biology, Austrian Academy of Sciences, Vienna, Austria
   2. Department of Biological Chemistry and Metabolism, John Innes Centre, Norwich, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review and editing

   For correspondence

   juan.concepcion@gmi.oeaw.ac.at

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7642-8375

2. Javier Vega Benjumea

   1. Department of Biological Chemistry and Metabolism, John Innes Centre, Norwich, United Kingdom
   2. Servicio de Bioquímica-Análisis clínicos, Hospital Universitario Puerta de Hierro, Madrid, Spain

   Contribution

   Funding acquisition, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

3. Aleksandra Bialas

   The Sainsbury Laboratory, University of East Anglia, Norwich, United Kingdom

   Contribution

   Formal analysis, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

4. Ryohei Terauchi

   1. Division of Genomics and Breeding, Iwate Biotechnology Research Center, Iwate, Japan
   2. Laboratory of Crop Evolution, Graduate School of Agriculture, Kyoto, Japan

   Contribution

   Funding acquisition, Writing – review and editing

   Competing interests

   No competing interests declared

5. Sophien Kamoun

   The Sainsbury Laboratory, University of East Anglia, Norwich, United Kingdom

   Contribution

   Conceptualization, Resources, Supervision, Writing – review and editing

   Competing interests

   SK receives funding from industry on NLR biology

   "This ORCID iD identifies the author of this article:" 0000-0002-0290-0315

6. Mark J Banfield

   Department of Biological Chemistry and Metabolism, John Innes Centre, Norwich, United Kingdom

   Contribution

   Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Writing – original draft, Writing – review and editing

   For correspondence

   mark.banfield@jic.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8921-3835

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