Unzipping the defense: a comprehensive review on bZIP transcription factors in Caenorhabditis elegans

Abstract

Caenorhabditis elegans is a simple yet powerful host model organism for exploring how animals mount defenses against infection. In the absence of an adaptive immune system, it relies solely on innate immunity, making it an ideal model for studying pathogen-induced innate immune responses, which are often conserved across higher eukaryotic organisms. Among the numerous transcription factors encoded in the C. elegans genome, the basic leucine zipper (bZIP) family is particularly notable for its pivotal role in regulating immune and stress responses. Of the 29 major bZIP proteins identified in C. elegans, this review focuses on 12 that play a direct role in pathogen response and innate immunity. In this review, we summarize the basic structure and processing of bZIP proteins, explore their potential involvement in various pathways that regulate innate immune and stress responses, and highlight key scientific questions for future investigation. By shedding light on the complex yet coordinated immune strategies employed by C. elegans this review offers insights to enhance our understanding of innate immunity in more complex organisms, including humans.

Keywords: C. elegans; bZIP transcription factors; innate immunity; nuclear localization; oxidative stress.

Figure 1

Multiple sequence alignment of bZIP proteins involved in pathogen response and innate immunity in C. elegans. The alignment displays conserved residues. Sequences were aligned using NCBI MSA viewer.

Figure 2

Basic structural features of bZIP protein. (A) Schematic representation of a bZIP protein, highlighting the α-helical regions, DNA-binding domain, and the leucine zipper motif. The figure was generated using BioRender software. (B) Predicted 3D structure of the representative bZIP protein ATF-7, generated using AlphaFold and visualized in ChimeraX. ATF-7 is one of the major well studied bZIPs in C. elegans due to its functional relevance under certain conditions including host-pathogen interactions and innate immunity. The structure illustrates the characteristic bZIP fold, including the DNA-binding and dimerization regions. (C) Annotated amino acid sequence of ATF-7, showing domain organization. The image was rendered using NetSurfP-3.0, indicating helices, zipper region, intrinsically disordered regions, and secondary structure elements.

Figure 3

Generalized processing and activation mechanism of bZIP proteins in response to pathogen exposure. Under normal conditions, bZIP proteins remain in an inactive or unstable form in the cytoplasm. Upon pathogen exposure, they undergo specific PTMs such as cleavage and/or phosphorylation which stabilize the protein and enable its activation. The processed bZIP protein translocates to the nucleus, where it binds to target DNA sequences and activates the transcription of antimicrobial genes or stress responsive genes. This regulatory cascade contributes to the host’s defense response against pathogen invasion including Pseudomonas sp.

Figure 4

Schematic representation of host immune response regulation in C. elegans. The diagram shows how bZIP transcription factors coordinate immune responses to infection in C. elegans upon infection compared to normal conditions. bZIP activation is influenced by multiple signaling cascades, including the p38-MAPK pathway and potentially other parallel or intersecting pathways. Crosstalk between these pathways is context-dependent and remains unclear. The other key questions remain unresolved such as the involvement of specific upstream regulators, how different pathogens modulate bZIP activity, and the nature of context-specific protein-protein interactions.