Emerging findings show critical non-apoptotic functions of caspases across diverse animal phyla. My unpublished findings indicate marked roles for caspases in ensuring multiple aspects of development including cell-cell communication, cell migration, protein homeostasis, and regulating the translation of a subset of genes in a tissue-specific manner. Moreover, my data indicate that a caspase target expressed in the same cell at the same time as the caspase may not be acted upon by the caspase until a specific developmental time point suggesting additional layers of regulation. It is not known how specific non- apoptotic caspase functions are mediated in such a dynamic manner. Based on my recent findings, it is likely that caspases require other components, such as E3 ligases, to execute the non-apoptotic functions. I therefore hypothesize that caspases function in complexes with other proteins that confer non-apoptotic specificity according to developmental stage, tissue type, and environmental status. Over the next five years, the critical goals for my lab are to: 1) identify the caspase-mediated regulatory network supporting vitality, 2) understand how protein-protein interactions influence distinct caspase mechanisms, and 3) identify the caspase targets mediating tissue-specific translational regulation. I have initiated an important collaboration with our biophysics core at UT Southwestern to vigorously undertake structure-function studies of caspases with UBR-type E3 ligases and other components. My proposed interdisciplinary studies include genetic screens, biochemical analyses, translatomics, proteomics, and structure-function studies. The objective of the proposed studies is to understand the conserved mechanisms directing the non- apoptotic caspase functions.
Emerging findings show unexpected non-cell death functions of caspases. I want to understand how these non-canonical caspase functions are regulated to account for the developmental stage, tissue type, and environmental status of an organism. The findings from this study will help us to understand mechanisms of caspases in development and stress responses that are important to ensure viability.
