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Host Defense and Parasite Evasion
Published in Eric S. Loker, Bruce V. Hofkin, Parasitology, 2023
Eric S. Loker, Bruce V. Hofkin
In some cases, plant parasites inoculate effector proteins into the cytoplasm of the plant cell. These effectors often have the ability to degrade host cell molecules that are essential “hubs” in the plant’s signaling pathways. As such, key signaling molecules are degraded and the plant’s defense response is effectively short-circuited. However, the plant immune system is very sensitive to the presence of effector proteins and it actively protects its signaling pathway molecules by producing another category of defense molecule, the NB-LRRs (nucleotide-binding, leucine-rich repeat proteins) (Figure 4.5). These are involved in the activation of signal pathway molecules that lead to downstream immune responses that are collectively referred to as effector-triggered immunity (ETI).
Serotonin and Melatonin in Root Morphogenesis
Published in Akula Ramakrishna, Victoria V. Roshchina, Neurotransmitters in Plants, 2018
Ramón Pelagio-Flores, Jesús Salvador López-Bucio, José López-Bucio
In rice transgenic plants expressing sheep serotonin N-acetyltransferase, increased melatonin production enhanced primary and seminal root growth (Park and Back 2012). Interestingly, follow-up studies in these plants revealed the differential expression of 464 genes, among the up-regulated genes transcription factors from the leucine-rich repeat and zinc-finger families were represented, whereas suppressed genes included jasmonate and senescence-associated genes (Byeon et al. 2013). The absence of auxin-regulated genes in the transcriptomes supports the idea that this neurotransmitter mediates its physiological responses likely acting independently or interfering with auxin.
The RAS System in Yeasts
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
The S. cerevisiae CYR1 was the first eukaryotic gene encoding adenylyl cyclase to be cloned.46 It encodes a 220 kDa protein that bears virtually no homology to the adenylyl cyclases which have since been characterized from higher eukaryotes.53 In particular, yeast adenylyl cyclases do not contain membrane-spanning domains. The S. pombe adenylyl cyclase resembles the S. cerevisiae form, both in structure109 and to some degree in regulation,49,50 although it is not regulated by RAS. The catalytic domain of the S. cerevisiae CYR1 comprises the terminal 40 kDa. The sequence is otherwise noteworthy for its large (60 kDa) leucine-rich repeat domain. This domain contains approximately 25 units of a 23 amino acid repeat with the consensus sequence PXXαXXLXXLXXLXLXXNXαXXα (where P represents proline, N aspara-gine, L leucine; a represents any aliphatic amino acid; and X represents any amino acid). This repeat motif is found in many apparently unrelated proteins encoded in genomes from yeasts to insects to vertebrates.31 It is not yet known if vertebrates contain a homolog of this form of adenylyl cyclase, but this appears likely (see below).
The BCL2/BAX/ROS pathway is involved in the inhibitory effect of astragaloside IV on pyroptosis in human umbilical vein endothelial cells
Published in Pharmaceutical Biology, 2022
Yi Su, Xin Yin, Xin Huang, Qianqian Guo, Mingyuan Ma, Liheng Guo
Indeed, the nucleotide-binding domain leucine-rich repeat-containing receptor (NLR) family protein NLRP3 plays a key role in host defence. It can be activated by many pathogen-derived, environmental and host-derived factors, including bacteria, viruses, fungi, dying cell components and crystal particles. Accumulating evidence suggests that the inflammasomes are involved in the pathogenesis of sepsis, especially NLRP3 (Wu et al. 2021). Inflammasomes trigger pyroptosis in a caspase-1-dependent manner (Xue et al. 2019). Pyroptosis is a rapid cell lysis mechanism following infection (Zychlinsky et al. 1992; Cookson and Brennan 2001) and involves endothelial cells and vascular smooth muscle cells (Pan et al. 2018; Zhang et al. 2018). Knockout of caspase-1 or caspase-11 protects mice from endotoxic shock (Li et al. 1995; Hagar et al. 2013; Kayagaki et al. 2015). The cytoplasmic delivery of lipopolysaccharide (LPS) activates caspase signalling and pyroptosis (Man et al. 2016; Vanaja et al. 2016). RIPK3 is also involved in pyroptosis (Grootjans et al. 2017). Caspase-11 activates gasdermin D, leading to pores in the cell membrane and lytic death by cell swelling (Broz 2015; Jorgensen and Miao 2015). Pyroptosis is involved in endothelial dysfunction and injury during sepsis (Singla and Machado 2018; Peng et al. 2020).
Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics
Published in Expert Opinion on Drug Discovery, 2021
Xuan Huang, Xiaoyong Zhang, Mengji Lu
Toll-like receptors (TLRs) are a group of the well-studied pattern recognition receptors [4]. They are highly conserved innate immune receptors present in multiple host cells and tissues. Since TLR4 and its ligand LPS were first discovered in 1997 and 1998, respectively, [5,6], other members of the TLR family and their corresponding ligands have been identified [7,8]. To date, 10 functional TLRs have been discovered in humans (TLRs 1–10), and a further three have been discovered that are expressed only in mice (TLRs 11–13) [9–11]. In humans, TLRs 1, 2, 4, 5, and 6 are mainly expressed on the cell surface, where they respond primarily to bacterial macromolecules including lipoproteins and LPS [12–15]. TLRs 3, 7, 8, 9, and 10 are located intracellularly, and they are activated mainly by foreign nucleic acids passed into cells during infection [16–20]. TLRs have an extracellular domain, a transmembrane domain, and a cytosolic toll-interleukin (IL)-1 receptor domain [21,22]. The extracellular domain is a leucine-rich repeat (LRR) region that can recognize and bind to pathogen-associated molecular patterns and DAMPs. The transmembrane domain and the cytosolic toll-IL-1 receptor domain coordinate downstream signaling pathways [23,24].
Small molecule agonists of toll-like receptors 7 and 8: a patent review 2014 – 2020
Published in Expert Opinion on Therapeutic Patents, 2020
Madeleine E. Kieffer, Akash M. Patel, Scott A. Hollingsworth, W. Michael Seganish
As illustrated throughout this review, there appears to be a common pharmacophore that is essential for receptor binding and activation (Figure 25). First, an aminopyrimidine, or cyclic variant thereof, forms key hydrogen-bonding interactions within both TLR7 and TLR8 receptors that have been confirmed through X-ray crystallographic structures [108,109,110,111]. Second, a linear or branching lipophilic tail fills the leucine rich repeat pocket within the protein. Finally, a benzylic or alkyl linker provides an exit vector to a solvent exposed area. Although this final motif is not always present, it can greatly improve potencies on both TLR7 and TLR8. These interactions are exemplified in Figure 25c, in which a model Novartis compound is docked into TLR7. While overall potency trends appear to remain consistent across scaffolds, tuning selectivity between TLR7 and TLR8 remains series-specific; subtle steric and geometric perturbations dictate selectivity. As we learn more about the efficacy of these molecules and further understand the new biology of TLRs, breaking away from this common pharmacophore and venturing into new chemical space could enable tunable agonist design and allow deeper exploration of TLR7 and TLR8 pharmacology.