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Modulation of Caenorhabditis elegans infection sensitivity by the LIN-7 cell junction protein.

ABSTRACT: In Caenorhabditis elegans, the LIN-2/7/10 protein complex regulates the activity of signalling proteins. We found that inhibiting lin-7 function, and also lin-2 and lin-10, resulted in enhanced C.?elegans survival after infection by Burkholderia spp., implicating a novel role for these genes in modulating infection outcomes. Genetic experiments suggested that this infection phenotype is likely caused by modulation of the DAF-2 insulin/IGF-1 signalling pathway. Supporting these observations, yeast two-hybrid assays confirmed that the LIN-2 PDZ domain can physically bind to the DAF-2 C-terminus. Loss of lin-7 activity also altered DAF-16 nuclear localization kinetics, indicating an additional contribution by hsf-1. Unexpectedly, silencing lin-7 in the hypodermis, but not the intestine, was protective against infection, implicating the hypodermis as a key tissue in this phenomenon. Finally, consistent with lin-7 acting as a general host infection factor, lin-7 mutants also exhibited enhanced survival upon infection by two other Gram-negative pathogens, Pseudomonas and Salmonella spp.

SUBMITTER: Sem X

PROVIDER: S-EPMC3470699 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Modulation of Caenorhabditis elegans infection sensitivity by the LIN-7 cell junction protein.

Sem Xiaohui X Kreisberg Jason F JF Kawli Trupti T Tan Man-Wah MW Rhen Mikael M Tan Patrick P

Cellular microbiology 20120621 10

In Caenorhabditis elegans, the LIN-2/7/10 protein complex regulates the activity of signalling proteins. We found that inhibiting lin-7 function, and also lin-2 and lin-10, resulted in enhanced C. elegans survival after infection by Burkholderia spp., implicating a novel role for these genes in modulating infection outcomes. Genetic experiments suggested that this infection phenotype is likely caused by modulation of the DAF-2 insulin/IGF-1 signalling pathway. Supporting these observations, yeas ...[more]

PMID: 22672310

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Project description:Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C. elegans, daf-16, promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16/FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p::gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p::gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p::gfp. Adult cell fate and the timing of col-19p::gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29. lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development, lin-41 opposes adult cell fate by inhibiting the translation of lin-29, which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p::gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p::gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41, but does not require lin-29. Taken together, this work demonstrates a novel role for daf-16/FOXO as a heterochronic gene that promotes expression of lin-41/TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model.

Project description:MBT domain proteins are involved in developmental processes and tumorigenesis. In vitro binding and mutagenesis studies have shown that individual MBT domains within clustered MBT repeat regions bind mono- and dimethylated histone lysine residues with little to no sequence specificity but discriminate against the tri- and unmethylated states. However, the exact function of promiscuous histone methyl-lysine binding in the biology of MBT domain proteins has not been elucidated. Here, we show that the Caenorhabditis elegans four MBT domain protein LIN-61, in contrast to other MBT repeat factors, specifically interacts with histone H3 when methylated on lysine 9, displaying a strong preference for di- and trimethylated states (H3K9me2/3). Although the fourth MBT repeat is implicated in this interaction, H3K9me2/3 binding minimally requires MBT repeats two to four. Further, mutagenesis of residues conserved with other methyl-lysine binding MBT regions in the fourth MBT repeat does not abolish interaction, implicating a distinct binding mode. In vivo, H3K9me2/3 interaction of LIN-61 is required for C. elegans vulva development within the synMuvB pathway. Mutant LIN-61 proteins deficient in H3K9me2/3 binding fail to rescue lin-61 synMuvB function. Also, previously identified point mutant synMuvB alleles are deficient in H3K9me2/3 interaction although these target residues that are outside of the fourth MBT repeat. Interestingly, lin-61 genetically interacts with two other synMuvB genes, hpl-2, an HP1 homologous H3K9me2/3 binding factor, and met-2, a SETDB1 homologous H3K9 methyl transferase (H3K9MT), in determining C. elegans vulva development and fertility. Besides identifying the first sequence specific and di-/trimethylation binding MBT domain protein, our studies imply complex multi-domain regulation of ligand interaction of MBT domains. Our results also introduce a mechanistic link between LIN-61 function and biology, and they establish interplay of the H3K9me2/3 binding proteins, LIN-61 and HPL-2, as well as the H3K9MT MET-2 in distinct developmental pathways.

Dataset Information

Modulation of Caenorhabditis elegans infection sensitivity by the LIN-7 cell junction protein.

Publications

Modulation of Caenorhabditis elegans infection sensitivity by the LIN-7 cell junction protein.

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