Components of the Ubiquitin Proteasome System are Required for the Nonapoptotic Death of the C. Elegans Linker Cell

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Zuckerman Malin, Jennifer
Life Sciences
thesis / dissertation description
Cell death is a major cell fate that promotes tissue sculpting and morphogenesis during animal development. Many developmental cell-culling events cannot be accounted for solely by caspase-dependent apoptosis, yet, alternate pathways are poorly understood. Direct evidence that caspase-independent non-apoptotic cell death pathways operate during animal development is provided by studies of the C. elegans linker cell. Genetic studies of linker cell death have led to the identification of genes that promote this process, including pqn-41, which encodes a glutamine-rich protein, as well as tir-1/TIRdomain and sek-1/MAPKK, which may function in the same pathway as pqn-41. The let- 7 microRNA and its indirect target, the Zn-finger transcription factor LIN-29, also promote linker cell death, and may act early in the process. Our work suggests that components of the ubiquitin proteasome system (UPS) act to promote linker cell death. We show that LET-70, an E2 ubiquitin-conjugating enzyme, is required cell-autonomously for linker cell death. LET-70 levels, as well as those of ubiquitin and some proteasome components, increase just before linker cell death initiation. This rise is dependent on an MLL-type histone methyltransferase complex and a MAPK cascade, whose activities are required for linker cell death. The E3 ligase components SIAH-1, RBX-1, and CUL-3 are also required for linker cell death and appear to act in the same pathway as let-70. We also identify the PLZF transcription factor EOR-1, and its accessory protein, EOR-2 as major regulators of linker cell death. Our studies suggest that EOR-1/2, as well as all known regulators of the linker cell death pathway may act upstream of UPS components to promote cell death. Our studies reveal that activation of the ubiquitin proteasome system is an important event promoting linker cell death. Given the morphological similarities between linker cell death and non-apoptotic developmental and pathological cell death in vertebrates, we raise the possibility that the proteasome may be a key mediator of vertebrate cell death.