The transcription factor ZIP-1 promotes resistance to intracellular infection in Caenorhabditis elegans

Vladimir Lažetić,Spencer S Gang,Fengting Wu,Ya-Ting Chang,Emily R Troemel,Kirthi C Reddy,Gira Bhabha,Lianne B Cohen

doi:10.1038/s41467-021-27621-w

Vladimir Lažetić, Spencer S Gang + Show 6 more

Open Access

https://doi.org/10.1038/s41467-021-27621-w

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Journal: Nature Communications	Publication Date: Jan 10, 2022
Citations: 26	License type: open-access

Affiliation: New York University

Abstract

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts; specifically, the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans remain understudied. Two different types of intracellular pathogens that naturally infect the C. elegans intestine are the Orsay virus, which is an RNA virus, and microsporidia, which comprise a phylum of fungal pathogens. Despite their molecular differences, these pathogens induce a common host transcriptional response called the intracellular pathogen response (IPR). Here we show that zip-1 is an IPR regulator that functions downstream of all known IPR-activating and regulatory pathways. zip-1 encodes a putative bZIP transcription factor, and we show that zip-1 controls induction of a subset of genes upon IPR activation. ZIP-1 protein is expressed in the nuclei of intestinal cells, and is at least partially required in the intestine to upregulate IPR gene expression. Importantly, zip-1 promotes resistance to infection by the Orsay virus and by microsporidia in intestinal cells. Altogether, our results indicate that zip-1 represents a central hub for triggers of the IPR, and that this transcription factor has a protective function against intracellular pathogen infection in C. elegans.

Highlights

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts; the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans remain understudied
Using two RNA interference (RNAi) screens, we find that the gene encoding a putative basic region-leucine zipper transcription factor called zip-1 plays a role in activating expression of the intracellular pathogen response (IPR) gene pals-5 by all known IPR triggers
To determine which transcription factor(s) activates IPR gene expression, we screened an RNAi library composed of 363 RNAi clones targeting 357 predicted transcription factors to identify RNAi clones that repress constitutive expression of the PALS-5::GFP translational reporter in a pals-22(jy3) background

Summary

Introduction

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts; the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans remain understudied. N. parisii is a species of Microsporidia, which comprise a phylum of obligate intracellular fungal pathogens that infect a large range of animal hosts including humans It is not known which host receptors detects N. parisii infection, but the DRH-1 RIG-I-like receptor appears to detect viral RNA replication products, and to be critical for viral induction of the IPR10. While intracellular infection by the Orsay virus or by N. parisii cause hallmarks of proteotoxic stress in C. elegans intestinal cells[11], genetic and kinetic analyses indicate that proteotoxic stress is activating IPR gene expression in parallel to viral infection, and that there are several independent triggers of the IPR10.

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