Effector and regulator: Diverse functions of C. elegans C-type lectin-like domain proteins

In C. elegans, 283 clec genes encode a highly diverse family of C-type lectin-like domain (CTLD) proteins. Since vertebrate CTLD proteins have characterized functions in defense responses against pathogens and since expression of C. elegans clec genes is pathogen-dependent, it is generally assumed that clec genes function in C. elegans immune k. However, little is known about the relative contribution and exact function of CLEC proteins in C. elegans immunity. Here, we focused on the C. elegans clec gene clec-4, whose expression is highly upregulated by pathogen infection, and its paralogs clec-41 and clec-42. We found that, while mutation of clec-4 resulted in enhanced resistance to the Gram-positive pathogen Bacillus thuringiensis MYBt18247 (Bt247), inactivation of clec-41 and clec-42 by RNAi enhanced susceptibility to Bt247. Further analyses revealed that enhanced resistance of clec-4 mutants to Bt247 was due to an increase in feeding cessation on the pathogen and consequently a decrease in pathogen load. Moreover, clec-4 mutants exhibited feeding deficits also on non-pathogenic bacteria that were in part reflected in the clec-4 gene expression profile, which overlapped with gene sets affected by starvation or mutation in nutrient sensing pathways. However, loss of CLEC-4 function only mildly affected life-history traits such as fertility, indicating that clec-4 mutants are not subjected to dietary restriction. While CLEC-4 function appears to be associated with the regulation of feeding behavior, we show that CLEC-41 and CLEC-42 proteins likely function as bona fide immune effector proteins that have bacterial binding and antimicrobial capacities. Together, our results exemplify functional diversification within clec gene paralogs. Author summary C-type lectin-like domain (CTLD) containing proteins fulfill various and fundamental tasks in the human and mouse immune system. Genes encoding CTLD proteins are present in all animal genomes, in some cases in very large numbers and highly diversified. While the function of several vertebrate CTLD proteins is well characterized, experimental evidence of an immune function of most invertebrate CTLD proteins is missing, although their role in immunity is usually assumed. We here explore the immune function of three related CTLD proteins in the model nematode Caenorhabditis elegans. We find that they play diverse roles in C. elegans immunity, functioning as antimicrobial immune effector proteins that are important for defense against pathogen infection and probably directly interact with bacteria, but also regulators of feeding behavior that more indirectly affect C. elegans pathogen resistance. Such insight into the functional consequence of invertebrate CTLD protein diversification contributes to our understanding of the evolution of innate and invertebrate immune systems.

Automated summary

The study focused on C. elegans CLEC proteins, specifically clec-4, clec-41, and clec-42, and found that they play diverse roles in immunity. CLEC-4 functions in regulating feeding behavior to enhance resistance, while CLEC-41 and CLEC-42 act as antimicrobial proteins directly interacting with bacteria to defend against pathogen infection. The functional diversification of CLEC gene paralogs contributes to understanding the evolution of innate and invertebrate immune systems.