Skip to main content
Open Access Publications from the University of California


UC San Francisco Electronic Theses and Dissertations bannerUCSF

Otubain 1 in T cell homeostasis and programmed cell death

  • Author(s): Lee, Albert Chuh-kai
  • Advisor(s): Ma, Averil I
  • et al.

Ubiquitination is a process used by cells to tightly control signaling pathways by covalently attaching a ubiquitin molecule to a target substrate. This process is reversible by the activity of deubiquitinating enzymes. Otubain 1 (Otub1) is a novel deubiquitinating enzyme whose physiologic relevance in an in vivo setting had not been described. In this dissertation, we describe two novel functions of Otub1, discovered after creating and analyzing Otub1-deficient (Otub1-/-) mice.

We first found that Otub1-/- mice die during late embryonic development. To examine whether Otub1 plays a role in the functioning of immune cells, we reconstituted irradiated recipients with Otub1-/- fetal livers to create chimera. At baseline in the absence of overt stimulation, Otub1-/- chimera had more memory-phenotype CD8+ T cells than wildtype and T cell homeostasis was disrupted in a cell-intrinsic manner. Otub1-/- T cells also hyperrespond to homeostatic signals, particularly IL7 stimulation.

While studying Otub1's role in T cell homeostasis, we also discovered it had a role in regulating programmed cell death. Using mouse embryonic fibroblasts (MEFs) and a human cell line, we found that Otub1-deficiency or Otub1 knockdown sensitizes the cell to undergo more TNF-induced apoptosis and necroptosis. Specifically, Otub1-deficiency led to increased formation of the necrosome, the Rip3-containing complex that drives necroptosis. This function may in part be driven by an accelerated loss of cellular inhibitor of apoptosis protein-1 (c-IAP1) in Otub1-/- cells as compared to wildtype. Together, we have shown that Otub1 has important in vivo roles in regulating T cell homeostasis and programmed cell death. Along with other studies, this work establishes Otub1 as a critical regulator of diverse signaling pathways and opens up several future avenues of investigation.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View