A pals-25 gain-of-function allele triggers systemic resistance against natural pathogens of C. elegans

Abstract

Regulation of immunity throughout an organism is critical for host defense. Previous studies in the nematode Caenorhabditis elegans have described an “ON/OFF” immune switch comprised of the antagonistic paralogs PALS-25 and PALS-22, which regulate resistance against intestinal and epidermal pathogens. Here, we identify and characterize a PALS-25 gain-of-function mutant protein with a premature stop (Q293*), which we find is freed from physical repression by its negative regulator, the PALS-22 protein. PALS-25(Q293*) activates two related gene expression programs, the Oomycete Recognition Response (ORR) against natural pathogens of the epidermis, and the Intracellular Pathogen Response (IPR) against natural intracellular pathogens of the intestine. A subset of ORR/IPR genes is upregulated in pals-25(Q293*) mutants, and they are resistant to oomycete infection in the epidermis, and microsporidia and virus infection in the intestine, but without compromising growth. Surprisingly, we find that activation of PALS-25 seems to primarily stimulate the downstream bZIP transcription factor ZIP-1 in the epidermis, with upregulation of gene expression in both the epidermis and in the intestine. Interestingly, we find that PALS-22/25-regulated epidermal-to-intestinal signaling promotes resistance to the N. parisii intestinal pathogen, demonstrating cross-tissue protective immune induction from one epithelial tissue to another in C. elegans.

Multiplepalsgene modules control a balance between immunity and development inCaenorhabditis elegans

“…Instead, we harvested a population of animals with the average stage of L4 that also contained some older and younger animals. In differential expression analysis of our RNA-seq data, we found that 3,001 genes were upregulated in pals-17 mutants compared to wild-type animals, which significantly overlap with previously defined IPR genes (70/80 IPR genes) and genes upregulated in pals-22(jy3) mutants (262/457) (5) (Fig 4A, S1, S3 and S4 Tables). However, many of the differentially expressed genes in pals-17 mutants could be due to the wide range of developmental ages found in a population of these mutants (S3 Fig).…”

“…All previously described triggers require ZIP-1 for induction of the pals-5p::GFP reporter. Here, we found that pals-17 RNAi induces expression of ZIP-1::GFP in intestinal nuclei (Fig S1), which also occurs in response to several other IPR triggers (5,14).…”

“…Specifically, the jy74 allele, with guanine 325 mutated into adenine, is predicted to affect splicing between the third and fourth exons of pals-17. pals-17, like pals-22 and pals-25, belongs to the clade of pals genes that are not induced upon intracellular infection (4)(5)(6)(7). To confirm that the mutation in pals-17 is responsible for the upregulated expression of the pals-5p::GFP reporter, we introduced a fosmid containing a wild-type copy of pals-17 into pals-22(-) pals-25(-) pals-17(jy74) mutants.…”

“…Recently, we described a genetic switch in the nematode C. elegans that regulates a balance between growth and immunity (4, 5). Through forward genetic screening, we found that the pals-22 gene represses a set of immunity-related genes called the Intracellular Pathogen Response (IPR) genes, which are activated upon infection by natural intracellular pathogens of the C. elegans intestine – the Orsay virus and the fungus Nematocida parisii from the microsporidia phylum (6-10).…”

“…to a lesser degree than the loss of pals-17(4)(5)(6). Although pals-22(jy1) and pals-17(*) alleles have premature stop codons in similar regions of pals-22 and pals-17, developmental impairment is more severe in pals-17(*) animals.…”