Unusual Regulation of a STAT Protein by an SLC6 Family Transporter in C. elegans Epidermal Innate Immunity

Abstract

The cuticle and epidermis of Caenorhabditis elegans provide the first line of defense against invading pathogens. Upon invasion by the fungal pathogen Drechmeria coniospora, C. elegans responds by upregulating the expression of antimicrobial peptides (AMPs) in the epidermis via activation of at least two pathways, a neuroendocrine TGF-β pathway and a p38 MAPK pathway. Here, we identify the sodium-neurotransmitter symporter SNF-12, a member of the solute carrier family (SLC6), as being essential for both these immune signaling pathways. We also identify the STAT transcription factor-like protein STA-2 as a direct physical interactor of SNF-12 and show that the two proteins function together to regulate AMP gene expression in the epidermis. Both SNF-12 and STA-2 act cell autonomously and specifically in the epidermis to govern the transcriptional response to fungal infection. These findings reveal an unorthodox mode of regulation for a STAT factor and highlight the molecular plasticity of innate immune signaling.

A SLC6 transporter of the novel B0,- system aids in absorption and detection of nutrient amino acids in Caenorhabditis elegans

“…These include: snf-6 (Kim et al, 2004), snf-11 (Mullen et al, 2006), mod-5 (Ranganathan et al, 2001) and dat-1 (Jayanthi et al, 1998), which encode putative acetylcholine, GABA, serotonin and dopamine transporters, respectively. An essential role in immune signaling has been also been demonstrated for snf-12 (Dierking et al, 2011). However, the substrates of this transporter remain unknown.…”

“…However, the substrates of this transporter remain unknown. Phylogenomic trees of the SLC6 family including nematode representatives have been published previously (Boudko et al, 2005a;Meleshkevitch et al, 2009b;Boudko, 2010;Dierking et al, 2011). The phylogenomic analysis presented in this work focuses on identification of NAT homologs and includes additional nematode species.…”

Evolution of Cytokine Receptor Signaling

“…This protein family has ancient roots, with the most divergent being the plant GRAS proteins, which possess an SH2-like domain and a putative DNA-binding domain (27), whereas present-day slime mold possess a STAT-like protein that includes a coiled-coil domain involved in transcriptional regulation added via domain accretion (28,29). The N-terminal and C-terminal transactivation domains formed later (30)(31)(32)(33), with a definitive archetypal STAT clearly identifiable in bilateria (11,34), as exemplified in the present-day fruit fly Marelle protein (34), which is most homologous to higher vertebrate STAT5 and STAT6. SHPs.…”

Antimicrobial effectors in the nematode Caenorhabditis elegans : an outgroup to the Arthropoda

“…While the upstream activators of C. elegans immune signalling cascades are less well understood, several downstream transcription factors that regulate the activation of immune effector gene expression following infection with different pathogens have been identified. For example, the basic helix-loop-helix (bHLH) transcription factor HLH-30 (TFEB in mammals) was demonstrated to regulate expression of effector genes in response to S. aureus [23], the GATA transcription factor ELT-2 (homologous to human GATA-4, -5 and -6) in response to P. aeruginosa [24], and the signal transducer and activator of transcription (STAT)-like transcription factor STA-2 in response to D. coniospora [25]. Caenorhabditis elegans immune effector mechanisms, which function in pathogen elimination, have been characterized in several cases, as explained in more detail in §2.…”

“…The main exception refers to nlp-29, for which an endogenous danger signal triggers gene expression [46] and which is regulated through a complex signalling network (e.g. [21,25,45,46]). Further analysis of the exact regulation of antimicrobial effector genes would be of great value for understanding their role in defence.…”