" A NRF2-induced secretory phenotype activates immune surveillance to remove irreparably damaged cells” 

Click here to join the meeting  

Host: Prof Simon Arthur

Abstract  

The KEAP1-NRF2 pathway is a cytoprotective pathway which allows cells to respond and adapt to a broad range of toxic chemical stimuli. KEAP1 is an E3 ubiquitin ligase adapter which, under basal non-stressed conditions, targets the transcription factor NRF2 for ubiquitination and proteasome-dependent degradation. The KEAP1 protein is equipped with a number of highly reactive cysteine-based sensors which allow it to directly sense and bind to electrophiles and oxidants. The triggering of these sensors inactivates KEAP1, resulting in nuclear accumulation of NRF2, and the transcriptional upregulation of a network of genes encoding cytoprotective proteins.

In response to irreparable cellular damage, I recently found that activation of NRF2 results in the upregulation of a unique secretory transcriptional program, which I named the NRF2-Induced Secretory Phenotype, or NISP. Genetic mouse models revealed that the function of the NISP is to recruit immune effector cells, including CCR2+ classical monocytes, to the site of tissue damage so that the irreparably damaged cells can be safely removed through phagocytosis or efferocytosis. This model represents the termination of the oxidative stress response under conditions in which the cellular damage cannot be repaired, as otherwise, the maintenance of damage cells in situ would be deleterious for organismal survival due to the potentially cancerous nature of the damaged cells.

In this seminar, I will introduce the NRF2-NISP-Immune surveillance model, and discuss some of the implications of this model in relation to cancer development, anti-cancer drug strategies and anti-viral responses.