Induced proximity of a TIR signaling domain on a plant-mammalian NLR chimera activates defense in plants

Abstract

Plant and animal intracellular nucleotide-binding, leucine-rich repeat (NLR) immune receptors detect pathogen-derived molecules and activate defense. Plant NLRs can be divided into several classes based upon their N-terminal signaling domains, including TIR (Toll-like, Interleukin-1 receptor, Resistance protein)- and CC (coiled-coil)-NLRs. Upon ligand detection, mammalian NAIP and NLRC4 NLRs oligomerize, forming an inflammasome that induces proximity of its N-terminal signaling domains. Recently, a plant CC-NLR was revealed to form an inflammasome-like hetero-oligomer. To further investigate plant NLR signaling mechanisms, we fused the N-terminal TIR domain of several plant NLRs to the N terminus of NLRC4. Inflammasome-dependent induced proximity of the TIR domain in planta initiated defense signaling. Thus, induced proximity of a plant TIR domain imposed by oligomerization of a mammalian inflammasome is sufficient to activate authentic plant defense. Ligand detection and inflammasome formation is maintained when the known components of the NLRC4 inflammasome is transferred across kingdoms, indicating that NLRC4 complex can robustly function without any additional mammalian proteins. Additionally, we found NADase activity of a plant TIR domain is necessary for plant defense activation, but NADase activity of a mammalian or a bacterial TIR is not sufficient to activate defense in plants.

Antiviral activity of bacterial TIR domains via signaling molecules that trigger cell death

“…Our data show that TIR domains in the Thoeris anti phage defense systems produce a signaling molecule that activates the associated effector to abort phage infection. Similar molecules produced by plant TIR domains were recently hypothesized to serve as secondary messengers for plant immunity, but their exact roles in plants and their putative receptors are currently unknown 6,7 . Our results verify that TIR-derived cADPR isomers can serve as immune secondary messengers, and can inform future studies in plant model systems to reveal the role of such TIR-produced molecules in the plant immune response to pathogens.…”

“…Activation of plant TIRs leads to a form of cell suicide known as the hypersensitive response, which prevents pathogen propagation 5 . The mechanism through which v-cADPR production promotes cell death in plants is currently unknown 6,7 .…”

Recent Advances in Effector-Triggered Immunity in Plants: New Pieces in the Puzzle Create a Different Paradigm

“…The accumulation of enzymatic products, such as variant-cyclic ADP-Ribose (v-cADPR), ADP-Ribose, and nicotinamide, which are necessary for immune signaling, are proposed to be downstream of TIR-enzyme activation. The NADase activity of the plant TIR domain is solely required for plant immunity, since the fusion of plant TIR (not animal or bacterial TIR) to the mammalian NLR Family CARD Domain Containing 4 activates immune signaling in plants [ 87 ]. Interestingly, in both enhanced disease susceptibility 1 ( eds1 ) and n requirement gene 1 ( nrg1 ) mutants, the activation of RBA1 accumulates v-cADPR but fails to induce a cell-death response [ 86 ], indicating that the accumulation of enzymatic products happens upstream of EDS1-NRG1.…”

Disentangling cause and consequence: Genetic dissection of theDANGEROUS MIX2risk locus, and activation of the DM2h NLR in autoimmunity

“…In the resistosome formed by activated Roq1, two dimers of TIR domain dimers exhibit a two-fold symmetry. This conformation leads to opening of the NADase active site of the TIR domain and breakdown of NAD + (Horsefield et al, 2019; Wan et al, 2019; Duxbury et al, 2020; Martin et al, 2020b). In the latter case, it is assumed that one of the breakdown products of the TIR domain enzymatic activity, whose molecular identity remains to be determined, functions as a signaling molecule.…”