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Leucine-rich repeats and calponin homology containing 4 (Lrch4) regulates the innate immune response.

ABSTRACT: Toll-like receptors (TLRs) are pathogen-recognition receptors that trigger the innate immune response. Recent reports have identified accessory proteins that provide essential support to TLR function through ligand delivery and receptor trafficking. Herein, we introduce leucine-rich repeats (LRRs) and calponin homology containing 4 (Lrch4) as a novel TLR accessory protein. Lrch4 is a membrane protein with nine LRRs in its predicted ectodomain. It is widely expressed across murine tissues and has two expression variants that are both regulated by lipopolysaccharide (LPS). Predictive modeling indicates that Lrch4 LRRs conform to the horseshoe-shaped structure typical of LRRs in pathogen-recognition receptors and that the best structural match in the protein database is to the variable lymphocyte receptor of the jawless vertebrate hagfish. Silencing Lrch4 attenuates cytokine induction by LPS and multiple other TLR ligands and dampens the in vivo innate immune response. Lrch4 promotes proper docking of LPS in lipid raft membrane microdomains. We provide evidence that this is through regulation of lipid rafts as Lrch4 silencing reduces cell surface gangliosides, a metric of raft abundance, as well as expression and surface display of CD14, a raft-resident LPS co-receptor. Taken together, we identify Lrch4 as a broad-spanning regulator of the innate immune response and a potential molecular target in inflammatory disease.

SUBMITTER: Aloor JJ

PROVIDER: S-EPMC6369294 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Leucine-rich repeats and calponin homology containing 4 (Lrch4) regulates the innate immune response.

Aloor Jim J JJ Azzam Kathleen M KM Guardiola John J JJ Gowdy Kymberly M KM Madenspacher Jennifer H JH Gabor Kristin A KA Mueller Geoffrey A GA Lin Wan-Chi WC Lowe Julie M JM Gruzdev Artiom A Henderson Michael W MW Draper David W DW Merrick B Alex BA Fessler Michael B MB

The Journal of biological chemistry 20181206 6

Toll-like receptors (TLRs) are pathogen-recognition receptors that trigger the innate immune response. Recent reports have identified accessory proteins that provide essential support to TLR function through ligand delivery and receptor trafficking. Herein, we introduce leucine-rich repeats (LRRs) and calponin homology containing 4 (Lrch4) as a novel TLR accessory protein. Lrch4 is a membrane protein with nine LRRs in its predicted ectodomain. It is widely expressed across murine tissues and has ...[more]

PMID: 30523158

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Project description:BackgroundPlants are continuously challenged with biotic stress from environmental pathogens, and precise regulation of defense responses is critical for plant survival. Defense systems require considerable amounts of energy and resources, impairing plant growth, and plant hormones controlling transcriptional regulation play essential roles in establishing the appropriate balance between defense response to pathogens and growth. Chromatin regulators modulating gene transcription are broadly involved in regulating stress-responsive genes. However, which chromatin factors are involved in coordinating hormone signaling and immune responses in plants, and their functional mechanisms, remains unclear. Here, we identified a role of bromodomain-containing protein GTE4 in negatively regulating defense responses in Arabidopsis thaliana.ResultsGTE4 mainly functions as activator of gene expression upon infection with Pseudomonas syringe. Genome-wide profiling of GTE4 occupancy shows that GTE4 tends to bind to active genes, including ribosome biogenesis related genes and maintains their high expression levels during pathogen infection. However, GTE4 is also able to repress gene expression. GTE4 binds to and represses jasmonate biosynthesis gene OPR3. Disruption of GTE4 results in overaccumulation of jasmonic acid (JA) and enhanced JA-responsive gene expression. Unexpectedly, over-accumulated JA content in gte4 mutant is coupled with downregulation of JA-mediated immune defense genes and upregulation of salicylic acid (SA)-mediated immune defense genes, and enhanced resistance to Pseudomonas, likely through a noncanonical pathway.ConclusionsOverall, we identified a new role of the chromatin factor GTE4 as negative regulator of plant immune response through inhibition of JA biosynthesis, which in turn noncanonically activates the defense system against Pseudomonas. These findings provide new knowledge of chromatic regulation of plant hormone signaling during defense responses.

Dataset Information

Leucine-rich repeats and calponin homology containing 4 (Lrch4) regulates the innate immune response.

Publications

Leucine-rich repeats and calponin homology containing 4 (Lrch4) regulates the innate immune response.

Similar Datasets

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