Differential EDS1 requirement for cell death activities of plant TIR-domain proteins

Toll/interleukin-1 Receptor (TIR) domains are integral to immune systems across all domains of life. TIRs exist as single-domain and as larger receptor or adaptor proteins. In plants, TIRs constitute N-terminal domains of nucleotide-binding leucine-rich repeat (NLR) immune receptors. Although TIR-NLR and TIR signaling requires the Enhanced disease susceptibility 1 (EDS1) protein family, TIR domains persist in species that have incomplete or no EDS1 members. To assess whether particular TIR groups appear with EDS1, we searched for TIR-EDS1 co-occurrence patterns. Using a large-scale phylogenetic analysis of TIR domains from 39 algae and land plant species, we identify four conserved TIR groups, two of which are TIR-NLRs present in eudicots and two are more widespread. Presence of one TIR-only protein group is highly correlated with EDS1 and members of this group elicit EDS1-dependent cell death. By contrast, a more widely represented TIR group of TIR-NB-WD40/TPR (TNP) proteins (formerly called XTNX) has at least one member which can induce EDS1-independent cell death. Our data provide a new phylogeny-based plant TIR classification and identify TIR groups that appear to have evolved with and are dependent on EDS1, while others have EDS1-independent activity.

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

Science ◽

10.1126/science.aax1911 ◽

2019 ◽

Vol 365 (6455) ◽

pp. 793-799 ◽

Cited By ~ 79

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.

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

Science ◽

10.1126/science.aax1771 ◽

2019 ◽

Vol 365 (6455) ◽

pp. 799-803 ◽

Cited By ~ 69

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.

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Structural Evolution of TIR-Domain Signalosomes

Frontiers in Immunology ◽

10.3389/fimmu.2021.784484 ◽

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.

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

10.1101/2021.01.06.425286 ◽

2021 ◽

Author(s):

Gal Ofir ◽

Ehud Herbst ◽

Maya Baroz ◽

Daniel Cohen ◽

Adi Millman ◽

...

Keyword(s):

Cell Death ◽

Intracellular Signaling ◽

Interleukin 1 ◽

Signaling Molecules ◽

Immune Systems ◽

Tir Domain ◽

Cyclic Adp Ribose ◽

Molecular Signal ◽

Tir Domains ◽

Intracellular Signaling Molecules

AbstractThe Toll/interleukin-1 receptor (TIR) domain is a canonical component of animal and plant immune systems. In plants, intracellular pathogen sensing by immune receptors triggers their TIR domains to generate a molecule which is a variant of cyclic ADP-ribose (v-cADPR). This molecule is hypothesized to activate plant cell death via a yet unresolved pathway. TIR domains were recently also shown to be involved in a bacterial anti-phage defense system called Thoeris, but the mechanism of Thoeris defense remained unknown. In this study we report that phage infection triggers Thoeris TIR-domain proteins to produce an isomer of cyclic ADP-ribose. This molecular signal activates a second protein, ThsA, which then depletes the cell of the essential molecule nicotinamide adenine dinucleotide (NAD) and leads to abortive infection and cell death. We further show that similar to eukaryotic innate immune systems, bacterial TIR-domain proteins determine the immunological specificity to the invading pathogen. Our results describe a new antiviral signaling pathway in bacteria, and suggest that generation of intracellular signaling molecules is an ancient immunological function of TIR domains conserved in both plant and bacterial immunity.

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Multiple functional self-association interfaces in plant TIR domains

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1621248114 ◽

2017 ◽

Vol 114 (10) ◽

pp. E2046-E2052 ◽

Cited By ~ 55

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.

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

10.1101/2021.11.09.467869 ◽

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.

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Osteoprotegerin (OPG) protects pancreatic beta cells from Interleukin-1 induced cell death

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-2006-933037 ◽

2006 ◽

Vol 114 (S 1) ◽

Author(s):

J Schrader ◽

U Niebergall ◽

M Schoppet ◽

D Hörsch ◽

LC Hofbauer

Keyword(s):

Cell Death ◽

Beta Cells ◽

Pancreatic Beta Cells ◽

Interleukin 1

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EZ-ALBI Score for Predicting Hepatocellular Carcinoma Prognosis

Liver Cancer ◽

10.1159/000508971 ◽

2020 ◽

Vol 9 (6) ◽

pp. 734-743

Author(s):

Kazuya Kariyama ◽

Kazuhiro Nouso ◽

Atsushi Hiraoka ◽

Akiko Wakuta ◽

Ayano Oonishi ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Liver Function ◽

Large Scale ◽

Regression Coefficient ◽

Information Criterion ◽

Proportional Hazard ◽

Cox Proportional Hazard ◽

Highly Correlated ◽

Survival Risk ◽

Good Agreement

Introduction: The ALBI score is acknowledged as the gold standard for the assessment of liver function in patients with hepatocellular carcinoma (HCC). Unlike the Child-Pugh score, the ALBI score uses only objective parameters, albumin (Alb) and total bilirubin (T.Bil), enabling a better evaluation. However, the complex calculation of the ALBI score limits its applicability. Therefore, we developed a simplified ALBI score, based on data from a large-scale HCC database.We used the data of 5,249 naïve HCC cases registered in eight collaborating hospitals. Methods: We developed a new score, the EZ (Easy)-ALBI score, based on regression coefficients of Alb and T.Bil for survival risk in a multivariate Cox proportional hazard model. We also developed the EZ-ALBI grade and EZ-ALBI-T grade as alternative options for the ALBI grade and ALBI-T grade and evaluated their stratifying ability. Results: The equation used to calculate the EZ-ALBI score was simple {[T.Bil (mg/dL)] – [9 × Alb (g/dL)]}; this value highly correlated with the ALBI score (correlation coefficient, 0.981; p < 0.0001). The correlation was preserved across different Barcelona clinic liver cancer grade scores (regression coefficient, 0.93–0.98) and across different hospitals (regression coefficient, 0.98–0.99), indicating good generalizability. Although a good agreement was observed between ALBI and EZ-ALBI, discrepancies were observed in patients with poor liver function (T.Bil, ≥3 mg/dL; regression coefficient, 0.877). The stratifying ability of EZ-ALBI grade and EZ-ALBI-T grade were good and their Akaike’s information criterion values (35,897 and 34,812, respectively) were comparable with those of ALBI grade and ALBI-T grade (35,914 and 34,816, respectively). Conclusions: The EZ-ALBI score, EZ-ALBI grade, and EZ-ALBI-T grade are useful, simple scores, which might replace the conventional ALBI score in the future.

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An Insight into the Role of Apoptosis and Autophagy in Nitric Oxide–Induced Articular Chondrocyte Cell Death

Cartilage ◽

10.1177/1947603520976768 ◽

2020 ◽

pp. 194760352097676

Author(s):

Ekkapol Akaraphutiporn ◽

Takafumi Sunaga ◽

Eugene C. Bwalya ◽

Wang Yanlin ◽

Mwale Carol ◽

...

Keyword(s):

Nitric Oxide ◽

Cell Death ◽

Western Blot ◽

Cell Apoptosis ◽

Molecular Mechanisms ◽

Interleukin 1 ◽

Chondrocyte Apoptosis ◽

Protective Mechanism ◽

Autophagic Flux ◽

Qpcr Analysis

Objective To investigate the role and characterize the molecular mechanisms regulating apoptosis and autophagy in nitric oxide (NO)–induced chondrocyte cell death. Design Cell apoptosis and autophagy were evaluated in chondrocytes treated with sodium nitroprusside (SNP) combined with the presence or absence of interleukin-1 beta (IL-1β) and nutrient-deprived conditions. The concentration of nitrite was determined by Griess reaction. Activation of apoptosis and autophagy were determined by immunocytochemistry, Western blot, and quantitative real-time polymerase chain reaction (qPCR) analysis. Flow cytometry and MTT assay were used to assess cell viability. Results Cotreatment of chondrocytes with SNP and IL-1β under nutrient-deprived condition potentially enhanced the effect of NO-induced cell death. Immunocytochemistry, Western blot, and qPCR analysis indicated that treatment of chondrocytes with SNP significantly reduced autophagic activity, autophagic flux, and multiple autophagy-related (Atg) genes expression. These findings were associated with an increase in ERK, Akt, and mTOR phosphorylation, whereas autophagy induction through mTOR/p70S6K inhibition by rapamycin significantly suppressed NO-induced cell apoptosis. Furthermore, the cleavage of poly(ADP-ribose) polymerase (PARP) and caspase-3 activation in response to apoptosis was weakly detected. These results corresponded with a significant increase in apoptosis-inducing factor (AIF) expression, suggesting the involvement of the caspase-independent pathway. Conclusions These results demonstrate that in chondrocyte cultures with cells induced into an osteoarthritis state, NO inhibits autophagy and induces chondrocyte apoptosis mainly, but not completely through the caspase-independent pathway. Our data suggest that autophagy is a protective mechanism in the pathogenesis of osteoarthritis and could be proposed as a therapeutic target for degenerative joint diseases.

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Propagation of an MHD Shock in the Vicinity of a Magnetic Neutral Sheet

Symposium - International Astronomical Union ◽

10.1017/s0074180900067802 ◽

1980 ◽

Vol 91 ◽

pp. 323-326

Author(s):

D. J. Mullan ◽

R. S. Steinolfson

Keyword(s):

Magnetic Field ◽

Cosmic Rays ◽

Solar Corona ◽

Large Scale ◽

Field Structure ◽

Neutral Sheet ◽

Solar Cosmic Rays ◽

Magnetic Field Structure ◽

Large Scale Magnetic Field ◽

Highly Correlated

The acceleration of solar cosmic rays in association with certain solar flares is known to be highly correlated with the propagation of an MHD shock through the solar corona (Svestka, 1976). The spatial structure of the sources of solar cosmic rays will be determined by those regions of the corona which are accessible to the flare-induced shock. The regions to which the flare shock is permitted to propagate are determined by the large scale magnetic field structure in the corona. McIntosh (1972, 1979) has demonstrated that quiescent filaments form a single continuous feature (a “baseball stitch”) around the surface of the sun. It is known that helmet streamers overlie quiescent filaments (Pneuman, 1975), and these helmet streamers contain large magnetic neutral sheets which are oriented essentially radially. Hence the magnetic field structure in the low solar corona is characterized by a large-scale radial neutral sheet which weaves around the entire sun following the “baseball stitch”. There is therefore a high probability that as a shock propagates away from a flare, it will eventually encounter this large neutral sheet.

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