Biology subjects

Gildea, H. K.

Publications and source records attributed to Gildea, H. K..

2 recordsLinked to original sources

bioRxiv2022

SKN-1 is a metabolic surveillance factor that monitors amino acid catabolism to control stress resistance

The deleterious potential to generate oxidative stress and damage is a fundamental challenge to metabolism. The oxidative stress response transcription factor, SKN-1/NRF2, can sense and respond to changes in metabolic state, although the mechanism and physiological consequences of this remain unknown. To explore this connection, we performed a genetic screen in C. elegans targeting amino acid catabolism and identified multiple metabolic pathways as regulators of SKN-1 activity. We found that genetic perturbation of the conserved amidohydrolase T12A2.1/amdh-1 activates a unique subset of SKN-1 regulated detoxification genes. Interestingly, this transcriptional program is independent of canonical P38-MAPK signaling components but requires the GATA transcription factor ELT-3, nuclear hormone receptor NHR-49, and mediator complex subunit MDT-15. This activation of SKN-1 is dependent on upstream histidine catabolism genes HALY-1 and Y51H4A.7/UROC-1 and may occur through accumulation of a catabolite, 4-imidazolone-5-propanoate (IP). Triggering SKN-1 activation results in a physiological trade off of increased oxidative stress resistance but decreased survival to heat stress. Together, our data suggest that SKN-1 is a key surveillance factor which senses and responds to metabolic perturbations to influence physiology and stress resistance.

genetics↗

bioRxiv2022

Glia of C. elegans coordinate the heat shock response independent of the neuronal thermosensory circuit and serotonin

As organisms age, they lose the ability to induce appropriate stress responses, becoming vulnerable to protein toxicity and tissue damage. Neurons can signal to peripheral tissues to induce protective organelle-specific stress responses. Recent work has demonstrated a novel and independent role of glia in inducing such responses. Here, we show that overexpression of heat shock factor 1 (hsf-1) in the four astrocyte-like cephalic sheath cells of C. elegans is sufficient to induce a non-cell autonomous cytosolic unfolded protein response (UPR), also known as the heat shock response (HSR), in distal cells. These animals upregulate the HSR in peripheral cells and have increased lifespan and resistance to heat stress. This glial HSR regulation is independent of the canonical neuronal thermosensory circuit and of known neurotransmitters but is dependent on the small clear vesicle release protein UNC-13. Additionally, HSF-1 and the FOXO transcription factor DAF-16 are partially required in peripheral tissues for increase of non-autonomous HSR, lifespan, and thermotolerance. We find that cephalic sheath glial hsf-1 over-expression leads to increased pathogen resistance, which suggests a role for this signaling pathway in immune function.

neuroscience↗