Meta-Biol

• Pathways

The KEAP1:NFE2L2 (KEAP1-NRF2, Kelch-like ECH-associated protein 1-Nuclear Factor (erythroid-derived 2)-like 2) regulatory pathway plays a central role in protecting cells against multiple homeostatic responses including adaptation to oxidative, inflammatory, metabolic, proteotoxic and xenobiotic stresses. The NFE2L2 transcriptome has been implicated in protection against many chronic diseases including cardiovascular, metabolic, neurodgenerative and respiratory diseases (reviewed in Cuadrado et al, 2018; Baird and Yamamoto, 2020). In cancer, NFE2L2 plays a critical role in the metabolic reprogramming, directing metabolic intermediates into the Warburg and pentose phosphate pathways to support proliferative growth and redox homeostasis (reviewed in He et al, 2020; Ge et al, 2020; Hayes et al, 2020; Kitamura and Hotomashi, 2018)

KEAP1 is a redox sensor that together with CUL3/RBX1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NFE2L2 by targeting it for ubiquitination and proteasome-dependent degradation. Oxidative modifications or electrophile adduct formation with redox-sensitive cysteines within KEAP1 renders this protein unable to target bound NFE2L2 for ubiquitination and allows newly translated NFE2L2 to accumulate within the cell and translocate to the nucleus where it can promote its transcriptional program (reviewed in Cuadrado et al, 2019; Baird and Yamamoto, 2020).

Cells are subject to external molecular and physical stresses such as foreign molecules that perturb metabolic or signaling processes, and changes in temperature or pH. Cells are also subject to internal molecular stresses such as production of reactive metabolic byproducts. The ability of cells and tissues to modulate molecular processes in response to such stresses is essential to the maintenance of tissue homeostasis (Kultz 2005). Specific stress-related processes annotated here are cellular response to hypoxia, cellular response to heat stress, cellular senescence, HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand, response of EIF2AK1 (HRI) to heme deficiency, heme signaling, cellular response to chemical stress, cellular response to starvation, and unfolded protein response.

Individual cells detect and respond to diverse external molecular and physical signals. Appropriate responses to these signals are essential for normal development, maintenance of homeostasis in mature tissues, and effective defensive responses to potentially noxious agents (Kultz 2005). It is convenient, if somewhat arbitrary, to distinguish responses to signals involved in development and homeostasis from ones involved in stress responses, and that classification is followed here, with macroautophagy and responses to metal ions classified as responses to normal external stimuli, while responses to hypoxia, reactive oxygen species, and heat, and the process of cellular senescence are classified as stress responses. Signaling cascades are integral components of all of these response mechanisms but because of their number and diversity, they are grouped in a separate signal transduction superpathway in Reactome.