Student Theses and Dissertations

Date of Award

2018

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Shaham Laboratory

Abstract

Programmed cell death (PCD) is an important process in the development of multicellular organisms. Apoptosis, a form of PCD characterized morphologically by chromatin condensation, membrane blebbing, and cytoplasm compaction, and molecularly by the activation of caspase proteases, has been extensively investigated. Studies in C. elegans, Drosophila, mice, and the developing chick have revealed, however, that developmental PCD also occurs through other mechanisms, morphologically and molecularly distinct from apoptosis. One prominent cell death program, linker cell-type death (LCD), is morphologically conserved, and independent of the key genes that drive apoptosis. Instead, LCD functions, in part, through the stressrelated protein HSF-1, and subsequent upregulation of members of the ubiquitin proteasome system. How exactly HSF-1 is post-translationally regulated to either commit to cell survival or cell death is not currently known. Using a protein interaction screen and classical genetic studies, I propose that the homeodomain protein kinase HPK-1 is required to activate the heat shock function of HSF-1, thereby indirectly inhibiting its cell death role. I hypothesize that PQN-41C, a polyglutamine protein necessary for linker cell death, binds HPK-1 to limit its HSF-1 interactions, and pushes the cell towards death. Downstream of cell death, the linker cell must be phagocytosed and degraded by engulfing cells. This process does not rely on canonical apoptotic factors, so I carried out a forward genetic screen to identify genes involved in corpse degradation. I discovered a key protein network involved in linker cell corpse engulfment and degradation and revealed that two small GTPases, RAB-35 and ARF-6, and their regulators ensure timely phagocytosis and phagosome maturation. I also determined that the caspase CED-3 and its upstream regulator CED-4 are required not for cell death, but for proper cell corpse removal. This new role of caspase in cell corpse disposal offers an alternative function for the role of caspases in cell death, and suggests how apoptotic and non-apoptotic forms of cell death may work together to remove cells during animal development.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Available for download on Monday, April 13, 2020

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