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

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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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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Select targeting of intracellular Toll-interleukin-1 receptor resistance domains for protection against influenza-induced disease

Innate Immunity ◽

10.1177/1753425919846281 ◽

2020 ◽

Vol 26 (1) ◽

pp. 26-34

Author(s):

Kari Ann Shirey ◽

Wendy Lai ◽

Lindsey J Brown ◽

Jorge C G Blanco ◽

Robert Beadenkopf ◽

...

Keyword(s):

Immune Responses ◽

Intracellular Signaling ◽

Interleukin 1 ◽

Tir Domain ◽

Close Proximity ◽

Domain Interactions ◽

Tir Domains ◽

Molecular Patterns ◽

Lps Signaling

TLRs are a family of PRRs that respond to PAMPs or host-derived Danger-Associated Molecular Patterns (DAMPs) to initiate host inflammation and immune responses. TLR dimerization and recruitment of adapter molecules is critical for intracellular signaling and is mediated through intracellular Toll-Interleukin 1 Receptor Resistance (TIR) domain interactions. Human TIR domains, including reported structures of TIR1, TIR2, TIR6, TIR10, TIRAP, and MyD88, contain Cysteine (Cys) interactions or modifications that are disproportionally at, or near, reported biological TIR interfaces, or in close proximity to functionally important regions. Therefore, we hypothesized that intracellular TIR Cys regulation may have greater functional importance than previously appreciated. Expression of mutant TLR4-C747S or treatment of TLR4 reporter cells with a small molecule, Cys-binding inhibitor of TLR4, TAK-242, abrogated LPS signaling in vitro. Using TAK-242, mice were protected from lethal influenza challenge as previously reported for extracellular TLR4 antagonists. Molecular modeling and sequence analysis of the region surrounding TLR4-Cys747 indicate conservation of a WxxxE motif identified among bacterial and NAD+-consuming TIRs, as well as within the TIRs domains of surface TLRs 1, 2, 4, 6, and 10. Together, these data support the hypothesis that critical Cys within the TIR domain are essential for TLR4 functionality.

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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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Intracellular signaling molecules of nerve tissue progenitors as pharmacological targets for treatment of ethanol-induced neurodegeneration

Journal of Basic and Clinical Physiology and Pharmacology ◽

10.1515/jbcpp-2020-0317 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Gleb Nikolaevich Zyuz’kov ◽

Larisa Arkad`evna Miroshnichenko ◽

Elena Vladislavovna Simanina ◽

Larisa Alexandrovna Stavrova ◽

Tatyana Yur`evna Polykova

Keyword(s):

Stem Cells ◽

Alcohol Abuse ◽

Intracellular Signaling ◽

Signaling Molecules ◽

Growth Potential ◽

Nerve Tissue ◽

Intracellular Signaling Molecules

Abstract Objectives The development of approaches to the treatment of neurodegenerative diseases caused by alcohol abuse by targeted pharmacological regulation of intracellular signaling transduction of progenitor cells of nerve tissue is promising. We studied peculiarities of participation of NF-кB-, сАМР/РКА-, JAKs/STAT3-, ERK1/2-, p38-pathways in the regulation of neural stem cells (NSC) and neuronal-committed progenitors (NCP) in the simulation of ethanol-induced neurodegeneration in vitro and in vivo. Methods In vitro, the role of signaling molecules (NF-кB, сАМР, РКА, JAKs, STAT3, ERK1/2, p38) in realizing the growth potential of neural stem cells (NSC) and neuronal-committed progenitors (NCP) in ethanol-induced neurodegeneration modeled in vitro and in vivo was studied. To do this, the method of the pharmacological blockade with the use of selective inhibitors of individual signaling molecules was used. Results Several of fundamental differences in the role of certain intracellular signaling molecules (SM) in proliferation and specialization of NSC and NCP have been revealed. It has been shown that the effect of ethanol on progenitors is accompanied by the formation of a qualitatively new pattern of signaling pathways. Data have been obtained on the possibility of stimulation of nerve tissue regeneration in ethanol-induced neurodegeneration by NF-кB and STAT3 inhibitors. It has been found that the blockage of these SM stimulates NSC and NCP in conditions of ethanol intoxication and does not have a «negative» effect on the realization of the growth potential of intact progenitors (which will appear de novo during therapy). Conclusions The results may serve as a basis for the development of fundamentally new drugs to the treatment of alcoholic encephalopathy and other diseases of the central nervous system associated with alcohol abuse.

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