Enzymatic Functions for Toll/Interleukin-1 Receptor Domain Proteins in the Plant Immune System

Abstract

Rationally engineered improvements to crop plants will be needed to keep pace with increasing demands placed on agricultural systems by population growth and climate change. Engineering of plant immune systems provides an opportunity to increase yields by limiting losses to pathogens. Intracellular immune receptors are commonly used as agricultural disease resistance traits. Despite their importance, how intracellular immune receptors confer disease resistance is still unknown. One major class of immune receptors in dicots contains a Toll/Interleukin-1 Receptor (TIR) domain. The mechanisms of TIR-containing proteins during plant immunity have remained elusive. The TIR domain is an ancient module found in archaeal, bacterial and eukaryotic proteins. In animals, TIR domains serve a structural role by generating innate immune signaling complexes. The unusual animal TIR-protein, SARM1, was recently discovered to function instead as an enzyme that depletes cellular NAD + (nicotinamide adenine dinucleotide) to trigger axonal cell death. Two recent reports have found that plant TIR proteins also have the ability to cleave NAD +. This presents a new paradigm from which to consider how plant TIR immune receptors function. Here, we will review recent reports of the structure and function of TIR-domain containing proteins. Intriguingly, it appears that TIR proteins in all kingdoms may use similar enzymatic mechanisms in a variety of cell death and immune pathways. We will also discuss TIR structure-function hypotheses in light of the recent publication of the ZAR1 resistosome structure. Finally, we will explore the evolutionary context of plant TIR-containing proteins and their downstream signaling components across phylogenies and the functional implications of these findings.

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 .…”

Structure of the activated Roq1 resistosome directly recognizing the pathogen effector XopQ

“…4). The individual TIR domains interact with each other upon resistosome assembly, allowing them to become active NADases and trigger HR (38). The mechanisms for how this association renders TIRs catalytically active remains poorly understood.…”

“…S4), suggesting loss of NADase activity. Mechanistic details of NAD+ cleavage and product formation remain unresolved and have been found to vary among TIR domains (38). The steps in this enzymatic reaction involve breaking the glycosidic bond that connects nicotinamide to ADPR and, in some cases, a structural rearrangement in ADPR that leads to the formation of cyclic-ADPR or variant-cyclic-ADPR (12,49).…”

Reinventing the wheel with a synthetic plant inflammasome

“…Unlike the putative pore formation of the ZAR1 N-terminal CC, plant TIRs have recently been shown to be enzymes that cleave NAD + and NADP + (14, 15). TIR NADase function seems widely conserved across kingdoms and is found in a variety of proteins with cell death and immune functions (16). How this putative enzymatic NADase function activates downstream events is a major unanswered question for the plant immune system.…”