RT Journal Article
SR Electronic
T1 Mitochondrial unfolded protein response transcription factor ATFS-1 increases resistance to exogenous stressors through upregulation of multiple stress response pathways
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.04.26.441408
DO 10.1101/2021.04.26.441408
A1 Sonja K. Soo
A1 Annika Traa
A1 Meeta Mistry
A1 Jeremy M. Van Raamsdonk
YR 2021
UL http://biorxiv.org/content/early/2021/04/26/2021.04.26.441408.abstract
AB The mitochondrial unfolded protein response (mitoUPR) is an evolutionarily conserved pathway that responds to various insults to the mitochondria through transcriptional changes that restore mitochondrial homeostasis in order to facilitate cell survival. Gene expression changes resulting from the activation of the mitoUPR are mediated by the transcription factor ATFS-1/ATF-5. To further define the mechanisms through which the mitoUPR protects the cell during mitochondrial dysfunction, we characterized the role of ATFS-1 in responding to organismal stress. We found that activation of ATFS-1 is sufficient to cause upregulation of genes involved in multiple stress response pathways, including the DAF-16-mediated stress response pathway, the SKN-1-mediated oxidative stress response pathway, the HIF-mediated hypoxia response pathway, the p38-mediated innate immune response pathway, and antioxidant genes. Moreover, ATFS-1 is required for the upregulation of stress response genes after exposure to exogenous stressors, especially oxidative stress and bacterial pathogens. Constitutive activation of ATFS-1 increases resistance to multiple acute exogenous stressors, while disruption of atfs-1 decreases stress resistance. Although ATFS-1-dependent genes are upregulated in multiple long-lived mutants, constitutive activation of ATFS-1 in wild-type animals results in decreased lifespan. Overall, our work demonstrates that ATFS-1 serves a vital role in organismal survival of acute stresses through its ability to activate multiple stress response pathways, but that chronic ATFS-1 activation is detrimental for longevity.