HIF1, HSF1, and NRF2: Oxidant-Responsive Trio Raising Cellular Defenses and Engaging Immune System

Cellular homeostasis is continuously challenged by damage
from
reactive oxygen species (ROS) and numerous reactive electrophiles.
Human cells contain various protective systems that are upregulated
in response to protein damage by electrophilic or oxidative stress.
In addition to the NRF2-mediated antioxidant response, ROS and reactive
electrophiles also activate HSF1 and HIF1 that control heat shock
response and hypoxia response, respectively. Here, we review chemical
and biological mechanisms of activation of these three transcription
factors by ROS/reactive toxicants and the roles of their gene expression
programs in antioxidant protection. We also discuss how NRF2, HSF1,
and HIF1 responses establish multilayered cellular defenses consisting
of largely nonoverlapping programs, which mitigates limitations of
each response. Some innate immunity links in these stress responses
help eliminate damaged cells, whereas others suppress deleterious
inflammation in normal tissues but inhibit immunosurveillance of cancer
cells in tumors.