Biology subjects

Gang, S. S.

Publications and source records attributed to Gang, S. S..

3 recordsLinked to original sources

bioRxiv2023

Impairment of the SKN-1A/NRF1 proteasome surveillance pathway triggers tissue-specific protective immune responses against distinct natural pathogens in C. elegans.

Protein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF upregulates proteostasis capacity after blockade of the proteasome, and also promotes resistance against bacterial infection in the nematode C. elegans. SKN-1/NRF has three isoforms, and the SKN-1A/NRF1 isoform in particular regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants in skn-1a and its activating enzymes ddi-1 and png-1, show constitutive expression of immune response programmes against natural eukaryotic pathogens of C. elegans. These programmes are the Oomycete Recognition Response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the Intracellular Pathogen Response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently, skn-1a mutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programmes are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner, against natural eukaryotic pathogens of the C. elegans epidermis and intestine.

immunology↗

bioRxiv2022

A pals-25 gain-of-function allele triggers systemic resistance against natural pathogens of C. elegans

Regulation of immunity throughout an organism is critical for host defense. Previous studies in the nematode Caenorhabditis elegans have described an "ON/OFF" immune switch comprised of the antagonistic paralogs PALS-25 and PALS-22, which regulate resistance against intestinal and epidermal pathogens. Here, we identify and characterize a PALS-25 gain-of-function mutant protein with a premature stop (Q293*), which we find is freed from physical repression by its negative regulator, the PALS-22 protein. PALS-25(Q293*) activates two related gene expression programs, the Oomycete Recognition Response (ORR) against natural pathogens of the epidermis, and the Intracellular Pathogen Response (IPR) against natural intracellular pathogens of the intestine. A subset of ORR/IPR genes is upregulated in pals-25(Q293*) mutants, and they are resistant to oomycete infection in the epidermis, and microsporidia and virus infection in the intestine, but without compromising growth. Surprisingly, we find that activation of PALS-25 seems to primarily stimulate the downstream bZIP transcription factor ZIP-1 in the epidermis, which leads to upregulation of gene expression in both the epidermis and in the intestine. Interestingly, we find that this epidermal-to-intestinal signaling promotes resistance to the N. parisii intestinal pathogen, demonstrating cross-tissue protective immune induction from one epithelial tissue to another in C. elegans. Author summaryMulticellular organisms need to monitor the health and function of multiple tissues simultaneously to respond appropriately to pathogen infection. Here, we study an ON/OFF switch in the roundworm C. elegans that controls immune responses to diverse natural pathogens of the skin and gut. We show a physical association between the ON switch protein PALS-25 and the OFF switch protein PALS-22, and that this association is disrupted in a mutant, activated form of PALS-25. When either PALS-22 is lost, or PALS-25 is activated, a downstream immune regulator ZIP-1 is activated specifically in the skin but not the gut. Excitingly, our findings show that skin-specific loss of PALS-22 or skin-specific activation of PALS-25 can induce immune responses in the worm gut. These findings highlight the coordination of immune responses across different tissues that are commonly infected by microbial pathogens.

immunology↗

bioRxiv2021

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

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts. For example, almost nothing is known about the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans. Two types of intracellular pathogens that naturally infect the C. elegans intestine are the Orsay virus, which is a positive-sense RNA virus, and microsporidia, which are fungal pathogens. Surprisingly, these molecularly distinct pathogens induce a common host transcriptional response called the Intracellular Pathogen Response (IPR). Here we describe zip-1 as an IPR regulator that functions downstream of all known IPR activating and regulatory pathways. zip-1 encodes a putative bZIP transcription factor of previously unknown function, and we show how 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 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 all triggers of the IPR, and that this transcription factor plays a protective role against intracellular pathogen infection in C. elegans.

immunology↗