All synthesis of proteins occurs on ribosomes, and impairment of this process constitutes cellular stress.
The ribotoxic stress response (RSR) is one of three cellular maintenance systems that survey the structural and functional integrity of ribosomes. When presented with impaired ribosomes, the kinase ZAK-alpha phosphorylates and activates the kinases p38 and JNK to initiate inflammatory responses and/or induce programmed cell death. In addition, signaling though p38 and JNK has the potential to impact on cell differentiation, stress adaptation and metabolic regulation. However, despite decades of research into the RSR, the physiological relevance of the underlying pathway in whole organisms is unknown. In this project, I hypothesize that ribosomes are central cellular stress sensors and that the RSR constitutes a general stress response system. I aim to uncover the physiological and pathological implications of RSR impairment in diverse model organisms, such as mice, zebrafish and nematodes.
In one line of investigation, I am elucidating the connections between UV radiation to the skin and RSR-mediated cell death and inflammatory responses. These responses are relevant to many natural and pathological reactions in the skin, incl. sunburn, skin cancer development and tanning. I am also working towards understanding the spectrum of physiologically relevant perturbations that impair ribosomal translation and activates the RSR within our body. Finally, my work is focused on unravelling the molecular mechanism(s) underlying ribotoxic stress sensing by ZAK-alpha.
In sum, PHYRIST will yield the first detailed insight into the in vivo relevance of the ribotoxic stress response.
