The GCN-2/eIF-2α/ATF-4 signaling pathway regulates C. elegans defense against pathogen infection

ABSTRACT: In response to external or endogenous insults, eukaryotic cells can activate a common adaptive pathway called the integrated stress response (ISR). The ISR reduces global protein translation but upregulates the expression of stress response proteins to either restore cellular homeostasis or, in case of severe or prolonged stress, promote cell death. The bZIP transcription factor ATF4 plays a deciding role in cellular fate upon ISR activation, but the precise mechanisms underlying such decision-making remain unclear. Although bacterial infection has previously been observed to induce the ISR, the effects of this pathway on bacterial pathogenesis and host defense are not well understood. The functions of ATF4 in this process remain even more elusive. Using the Caenorhabditis elegans model to explore the bacterial infection-induced ISR, we found that infection with Salmonella enterica induced the GCN-2/eIF-2α/ATF-4 signaling pathway to modulate host defense against the infection. More specifically, ATF-4 suppressed the expression of ribosomal proteins in response to S. enterica exposure, reducing worm survival against the pathogen. Because ribosomal proteins are directly involved in protein translation, our data revealed an important, novel mechanism by which ATF-4 mediates the reduction of global translation under stress by inhibiting the expression of ribosomal proteins. ATF-4 also inhibited mitochondrial electron transport in response to S. enterica infection, likely functioning to dampen infection-induced production of reactive oxygen species. Moreover, our transcriptomic analysis showed that ATF-4 regulated the expression of collagens, a group of proteins that are tightly linked to stress resistance and longevity. Overall, we have identified specific molecular mechanisms by which ATF-4 determines cell fate upon ISR activation, providing a mechanistic understanding of how the bacterial infection-induced ISR impacts host physiology.

INSTRUMENT(S):

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Phillip Wibisono  

LAB HEAD: Dr. Jingru Sun

PROVIDER: PXD058186 | Pride | 2025-10-01

REPOSITORIES: Pride