scholarly journals TIR domains of plant immune receptors are NAD+-cleaving enzymes that promote cell death

Science ◽  
2019 ◽  
Vol 365 (6455) ◽  
pp. 799-803 ◽  
Author(s):  
Li Wan ◽  
Kow Essuman ◽  
Ryan G. Anderson ◽  
Yo Sasaki ◽  
Freddy Monteiro ◽  
...  
Keyword(s):  
Cell Death ◽  
Enzymatic Activity ◽  
Interleukin 1 ◽  
Adenosine Diphosphate ◽  
Immune Receptors ◽  
Cell Death Response ◽  
A Cell ◽  
Self Association ◽  
Activate Cell ◽  
Tir Domains

Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors activate cell death and confer disease resistance by unknown mechanisms. We demonstrate that plant Toll/interleukin-1 receptor (TIR) domains of NLRs are enzymes capable of degrading nicotinamide adenine dinucleotide in its oxidized form (NAD+). Both cell death induction and NAD+ cleavage activity of plant TIR domains require known self-association interfaces and a putative catalytic glutamic acid that is conserved in both bacterial TIR NAD+-cleaving enzymes (NADases) and the mammalian SARM1 (sterile alpha and TIR motif containing 1) NADase. We identify a variant of cyclic adenosine diphosphate ribose as a biomarker of TIR enzymatic activity. TIR enzymatic activity is induced by pathogen recognition and functions upstream of the genes enhanced disease susceptibility 1 (EDS1) and N requirement gene 1 (NRG1), which encode regulators required for TIR immune function. Thus, plant TIR-NLR receptors require NADase function to transduce recognition of pathogens into a cell death response.

scholarly journals Structural Evolution of TIR-Domain Signalosomes

2021 ◽  
Vol 12 ◽  
Author(s):  
Surekha Nimma ◽  
Weixi Gu ◽  
Natsumi Maruta ◽  
Yan Li ◽  
Mengqi Pan ◽  
...  
Keyword(s):  
Cell Death ◽  
Interleukin 1 ◽  
Structural Evolution ◽  
Functional Roles ◽  
Tir Domain ◽  
Cell Death Pathways ◽  
System A ◽  
Essential Components ◽  
Self Association ◽  
Tir Domains

TIR (Toll/interleukin-1 receptor/resistance protein) domains are cytoplasmic domains widely found in animals and plants, where they are essential components of the innate immune system. A key feature of TIR-domain function in signaling is weak and transient self-association and association with other TIR domains. An additional new role of TIR domains as catalytic enzymes has been established with the recent discovery of NAD+-nucleosidase activity by several TIR domains, mostly involved in cell-death pathways. Although self-association of TIR domains is necessary in both cases, the functional specificity of TIR domains is related in part to the nature of the TIR : TIR interactions in the respective signalosomes. Here, we review the well-studied TIR domain-containing proteins involved in eukaryotic immunity, focusing on the structures, interactions and their corresponding functional roles. Structurally, the signalosomes fall into two separate groups, the scaffold and enzyme TIR-domain assemblies, both of which feature open-ended complexes with two strands of TIR domains, but differ in the orientation of the two strands. We compare and contrast how TIR domains assemble and signal through distinct scaffolding and enzymatic roles, ultimately leading to distinct cellular innate-immunity and cell-death outcomes.

scholarly journals Multiple functional self-association interfaces in plant TIR domains

2017 ◽  
Vol 114 (10) ◽  
pp. E2046-E2052 ◽  
Author(s):  
Xiaoxiao Zhang ◽  
Maud Bernoux ◽  
Adam R. Bentham ◽  
Toby E. Newman ◽  
Thomas Ve ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Cell Death ◽  
Interleukin 1 ◽  
Tir Domain ◽  
Disease Resistance Protein ◽  
Resistance Protein ◽  
Cell Death Signaling ◽  
Self Association ◽  
Tir Domains ◽  
Diverse Plant

The self-association of Toll/interleukin-1 receptor/resistance protein (TIR) domains has been implicated in signaling in plant and animal immunity receptors. Structure-based studies identified different TIR-domain dimerization interfaces required for signaling of the plant nucleotide-binding oligomerization domain-like receptors (NLRs) L6 from flax and disease resistance protein RPS4 fromArabidopsis. Here we show that the crystal structure of the TIR domain from theArabidopsisNLR suppressor of npr1-1, constitutive 1 (SNC1) contains both an L6-like interface involving helices αD and αE (DE interface) and an RPS4-like interface involving helices αA and αE (AE interface). Mutations in either the AE- or DE-interface region disrupt cell-death signaling activity of SNC1, L6, and RPS4 TIR domains and full-length L6 and RPS4. Self-association of L6 and RPS4 TIR domains is affected by mutations in either region, whereas only AE-interface mutations affect SNC1 TIR-domain self-association. We further show two similar interfaces in the crystal structure of the TIR domain from theArabidopsisNLR recognition ofPeronospora parasitica1 (RPP1). These data demonstrate that both the AE and DE self-association interfaces are simultaneously required for self-association and cell-death signaling in diverse plant NLRs.

scholarly journals TIR domains of plant immune receptors are 2',3'-cAMP/cGMP synthetases mediating cell death

2021 ◽  
Author(s):  
Dongli Yu ◽  
Wen Song ◽  
Eddie Yong Jun Tan ◽  
Li Liu ◽  
Yu Cao ◽  
...  
Keyword(s):  
Cell Death ◽  
Immune Responses ◽  
Interleukin 1 ◽  
Structural Data ◽  
Negative Regulator ◽  
Synthetase Activity ◽  
Leucine Rich Repeat ◽  
Tir Domain ◽  
Immune Receptors ◽  
Tir Domains

2′,3′-cAMP is a positional isomer of the well-established second messenger 3′,5′-cAMP, but little is known on the biology of this noncanonical cyclic nucleotide monophosphate (cNMP). Toll/interleukin-1 receptor (TIR) domains of nucleotide-binding leucine-rich repeat (NLR) immune receptors have NADase function necessary but insufficient to activate plant immune responses. Here we show that plant TIR proteins, besides being NADases, act as 2′,3′-cAMP/cGMP synthetases by hydrolyzing RNA/DNA. Structural data shows that a TIR domain adopts distinct oligomers with dual and exclusive enzymatic activity. Mutations specifically disrupting the synthetase activity abrogate TIR-mediated cell death in Nicotiana benthamiana, supporting an important role for these cNMPs in TIR signaling. Furthermore, the Arabidopsis negative regulator of TIR-NLR signaling, NUDT7 displays 2′,3′-cAMP/cGMP but not 3′,5′-cAMP/cGMP phosphodiesterase activity and suppresses cell death activity of TIRs in N. benthamiana. Our study identifies a novel family of 2′,3′-cAMP/cGMP synthetase and establishes a role for the noncanonical cNMPs in plant immune responses.

scholarly journals Role of Ced-3/ICE-family proteases in staurosporine-induced programmed cell death.

1996 ◽  
Vol 133 (5) ◽  
pp. 1041-1051 ◽  
Author(s):  
M D Jacobsen ◽  
M Weil ◽  
M C Raff
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Mammalian Cell ◽  
Mammalian Cells ◽  
Apoptotic Cell ◽  
Interleukin 1 ◽  
Cell Types ◽  
Cysteine Proteases ◽  
A Cell ◽  
Bona Fide

In the accompanying paper by Weil et al. (1996) we show that staurosporine (STS), in the presence of cycloheximide (CHX) to inhibit protein synthesis, induces apoptotic cell death in a large variety of nucleated mammalian cell types, suggesting that all nucleated mammalian cells constitutively express all of the proteins required to undergo programmed cell death (PCD). The reliability of that conclusion depends on the evidence that STS-induced, and (STS + CHS)-induced, cell deaths are bona fide examples of PCD. There is rapidly accumulating evidence that some members of the Ced-3/Interleukin-1 beta converting enzyme (ICE) family of cysteine proteases are part of the basic machinery of PCD. Here we show that Z-Val-Ala-Asp-fluoromethylketone (zVAD-fmk), a cell-permeable, irreversible, tripeptide inhibitor of some of these proteases, suppresses STS-induced and (STS + CHX)-induced cell death in a wide variety of mammalian cell types, including anucleate cytoplasts, providing strong evidence that these are all bona fide examples of PCD. We show that the Ced-3/ICE family member CPP32 becomes activated in STS-induced PCD, and that Bcl-2 inhibits this activation. Most important, we show that, in some cells at least, one or more CPP32-family members, but not ICE itself, is required for STS-induced PCD. Finally, we show that zVAD-fmk suppresses PCD in the interdigital webs in developing mouse paws and blocks the removal of web tissue during digit development, suggesting that this inhibition will be a useful tool for investigating the roles of PCD in various developmental processes.

scholarly journals NAD+ cleavage activity by animal and plant TIR domains in cell death pathways

Science ◽  
2019 ◽  
Vol 365 (6455) ◽  
pp. 793-799 ◽  
Author(s):  
Shane Horsefield ◽  
Hayden Burdett ◽  
Xiaoxiao Zhang ◽  
Mohammad K. Manik ◽  
Yun Shi ◽  
...  
Keyword(s):  
Cell Death ◽  
Nicotinamide Adenine Dinucleotide ◽  
Interleukin 1 ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Effector Proteins ◽  
Nicotinamide Adenine ◽  
Cleavage Activity ◽  
Pathogen Effector ◽  
Cell Death Signaling ◽  
Tir Domains

SARM1 (sterile alpha and TIR motif containing 1) is responsible for depletion of nicotinamide adenine dinucleotide in its oxidized form (NAD+) during Wallerian degeneration associated with neuropathies. Plant nucleotide-binding leucine-rich repeat (NLR) immune receptors recognize pathogen effector proteins and trigger localized cell death to restrict pathogen infection. Both processes depend on closely related Toll/interleukin-1 receptor (TIR) domains in these proteins, which, as we show, feature self-association–dependent NAD+ cleavage activity associated with cell death signaling. We further show that SARM1 SAM (sterile alpha motif) domains form an octamer essential for axon degeneration that contributes to TIR domain enzymatic activity. The crystal structures of ribose and NADP+ (the oxidized form of nicotinamide adenine dinucleotide phosphate) complexes of SARM1 and plant NLR RUN1 TIR domains, respectively, reveal a conserved substrate binding site. NAD+ cleavage by TIR domains is therefore a conserved feature of animal and plant cell death signaling pathways.

scholarly journals Peptide-mediated Interference of TIR Domain Dimerization in MyD88 Inhibits Interleukin-1-dependent Activation of NF-κB

2005 ◽  
Vol 280 (16) ◽  
pp. 15809-15814 ◽  
Author(s):  
Maria Loiarro ◽  
Claudio Sette ◽  
Grazia Gallo ◽  
Andrea Ciacci ◽  
Nicola Fantò ◽  
...  
Keyword(s):  
Interleukin 1 ◽  
Cell System ◽  
Tir Domain ◽  
Loop Region ◽  
Good Target ◽  
A Cell ◽  
Tir Domains ◽  
Myeloid Differentiation Factor

Myeloid differentiation factor 88 (MyD88) plays a crucial role in the signaling pathways triggered by interleukin (IL)-1 and Toll-like receptors in several steps of innate host defense. A crucial event in this signaling pathway is represented by dimerization of MyD88, which allows the recruitment of downstream kinases like IRAK-1 and IRAK-4. Herein, we have investigated the function of the Toll/IL-1 receptor (TIR) domain in MyD88 homodimerization in cell-free andin vitroexperimental settings by using epta-peptides that mimic the BB-loop region of the conserved TIR domain of different proteins. By using a pull-down assay with purified glutathioneS-transferase-MyD88 TIR or co-immunoprecipitation experiments, we found that epta-peptides derived from the TIR domain of MyD88 and IL-18R are the most effective in inhibiting homodimerization with either the isolated TIR or full-length MyD88. Moreover, we demonstrated that a cell permeable analog of MyD88 epta-peptide inhibits homodimerization of MyD88 TIR domains in anin vitrocell system and significantly reduces IL-1 signaling, as assayed by activation of the downstream transcription factor NF-κB. Our results indicate that the BB-loop in TIR domain of MyD88 is a good target for specific inhibition of MyD88-mediated signalingin vivo.

scholarly journals Apoptosis-induced alkalinization by the Na+/H+ exchanger isoform 1 is mediated through phosphorylation of amino acids Ser726 and Ser729

2008 ◽  
Vol 295 (4) ◽  
pp. C883-C896 ◽  
Author(s):  
Amy L. Grenier ◽  
Khaled Abu-ihweij ◽  
Ge Zhang ◽  
Shannon Moore Ruppert ◽  
Rebecca Boohaker ◽  
...  
Keyword(s):  
Cell Death ◽  
P38 Map Kinase ◽  
Serine Phosphorylation ◽  
Targeted Mutagenesis ◽  
Mutant Form ◽  
Cytosolic Ph ◽  
Complex Process ◽  
Cell Death Response ◽  
Transient Rise ◽  
A Cell

Apoptosis is a complex process essential for normal tissue development and cellular homeostasis. While biochemical events that occur late in the apoptotic process are better characterized, early physiological changes that initiate the progression of cell death remain poorly understood. Previously, we observed that lymphocytes, undergoing apoptosis in response to growth factor withdrawal, experienced a rapid and transient rise in cytosolic pH. We found that the protein responsible was the pH-regulating, plasma membrane protein Na+/H+ exchanger isoform 1 (NHE1), and that its activity was impeded by inhibition of the stress-activated kinase, p38 MAP kinase. In the current study, we examined how NHE1 is activated during apoptosis. We identified the phosphorylation sites on NHE1 that regulate its alkalinizing activity in response to a cell death stimulus. Performing targeted mutagenesis, we observed that substitution of Ser726 and Ser729 for alanines produced a mutant form of NHE1 that did not alkalinize in response to an apoptotic stimulus, and expression of which protected cells from serum withdrawal- induced death. In contrast, substitution of Ser726 and Ser729 for glutamic acids raised the basal pH and induced susceptibility to death. Analysis of serine phosphorylation showed that phosphorylation of NHE1 during apoptosis decreased upon mutation of Ser726 and Ser729. Our findings thus confirm a necessary function for NHE1 during apoptosis and reveal the critical regulatory sites that when phosphorylated mediate the alkalinizing activity of NHE1 in the early stages of a cell death response.

scholarly journals Identification of Nicotiana benthamiana Genes Involved in Pathogen-Associated Molecular Pattern–Triggered Immunity

2010 ◽  
Vol 23 (6) ◽  
pp. 715-726 ◽  
Author(s):  
Suma Chakravarthy ◽  
André C. Velásquez ◽  
Sophia K. Ekengren ◽  
Alan Collmer ◽  
Gregory B. Martin
Keyword(s):  
Cell Death ◽  
Nicotiana Benthamiana ◽  
Large Scale ◽  
Forward Genetics ◽  
Hormone Signaling ◽  
Virus Induced Gene Silencing ◽  
Molecular Pattern ◽  
Cell Death Response ◽  
A Cell ◽  
Pathogen Associated Molecular Pattern

In order to identify components of pathogen-associated molecular pattern–triggered immunity (PTI) pathways in Nicotiana benthamiana, we conducted a large-scale forward-genetics screen using virus-induced gene silencing and a cell-death-based assay for assessing PTI. The assay relied on four combinations of PTI-inducing nonpathogens and cell-death-causing challenger pathogens and was first validated in plants silenced for FLS2 or BAK1. Over 3,200 genes were screened and 14 genes were identified that, when silenced, compromised PTI as judged by the cell-death-based assay. Further analysis indicated that the 14 genes were not involved in a general cell death response. A subset of the genes was found to act downstream of FLS2-mediated PTI induction, and silencing of three genes compromised production of reactive oxygen species in leaves exposed to flg22. The 14 genes encode proteins with potential functions in defense and hormone signaling, protein stability and degradation, energy and secondary metabolism, and cell wall biosynthesis and provide a new resource to explore the molecular basis for the involvement of these processes in PTI.

scholarly journals Common and distinct features of TIR domain function

2014 ◽  
Vol 70 (a1) ◽  
pp. C242-C242
Author(s):  
Simon Williams ◽  
Mohammed Alaidarous ◽  
Thomas Ve ◽  
Xiaoxiao Zhang ◽  
Eugene Valkov ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Paracoccus Denitrificans ◽  
Brucella Melitensis ◽  
Interleukin 1 ◽  
Adaptor Protein ◽  
Site Directed Mutagenesis ◽  
Tir Domain ◽  
Common Features ◽  
Self Association ◽  
Tir Domains

TIR (Toll/interleukin-1 receptor, resistance protein) domains feature in diverse proteins with functions in the immune system, such as animal TLRs (Toll-like receptors), plant NLRs (nucleotide binding, leucine-rich repeat) and bacterial virulence factors. It has been well established, especially through the work on TLRs, that signalling depends on regulated self-association of TIR domains. However, every single TIR domain structure has revealed a different association mode [1]. In the search for common features, we have targeted a number of TIR domains from mammals, plants and bacteria to characterize structurally. We have determined the crystal structures of the TIR domains from the human TLR adaptor protein MAL [1], the bacterial protein TcpB from Brucella melitensis [2] and the plant immune proteins L6 from flax [3] and SNC1, RPS4 and RRS1 from Arabidopsis (unpublished). In the case of the proteins RPS4 and RRS1, which work together as a protein complex to confer resistance to three different bacterial and fungal pathogens, we have determined, using linker-assisted crystallization, the first structure of a hetero-dimeric complex of TIR domains (Fig. 1). The association interface in this complex is conserved in the crystals of the TIR domains of RPS4 and RRS1 on their own, as well as in those of SNC1 and another Arabidopsis protein AT1G72930. Similarly, the dimerization interface observed in the structure of TcpB is conserved in the structure of the TIR domain-containing protein from Paracoccus denitrificans. We validated the association interfaces by site-directed mutagenesis coupled with a variety of cellular assays. As self-association is key to TIR domain function, our studies are finally revealing common features of the molecular function of TIR domains across phyla.

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