Proteolytic Mechanisms Mediating Diverse Non-Apoptotic Caspase Functions

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Project Summary 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 My unpublished findings indicate marked roles for caspases in ensuring multiple aspects of development including cell-cell communication, cell migration, protein homeostasis,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.