Immune cells must continually respond to external stimuli and adjust their levels of key regulatory proteins to transition between poised and active states. "Tagging" a protein with ubiquitin can improve interactions between proteins to promote signaling or initiate protein degradation. The goal of the Oliver Lab is to identify ubiquitin ligases and then use genetic, cellular, and biochemical approaches to define how those enzymes regulate immune cell function.
Some of the lab's efforts have focused on catalytic ubiquitin ligases of the Nedd4-family. The lab identified a small family of membrane-tethered adaptors, Ndfip1 and Ndfip2, that activate Nedd4-family ligases, and determined that these adaptors regulate T cell activation, CD4 differentiation and effector function, Treg cell metabolism, and lineage stability. The lab team combined this information on biologic function with biochemical data in which it defined precisely how these adaptors activate the enzymatic activity of Nedd4-family ligases; the lab is now using this information in the rational design of therapeutics. Based on the data, such therapeutics will be particularly useful in the treatment of autoimmune and/or allergic disease.
The Oliver Lab's recent work has employed systems biology approaches in which it has integrated transcriptome, proteome, and ubiquitome information to identify Cullin E3 ubiquitin ligases that are particularly active as T cells transition from resting to activated states. The lab has developed genetic models to test the biologic relevance of these ligases in protective immune responses. The lab is now poised to define how cullin ligases form distinct ubiquitin complexes in T cells or other immune cells and the unique set of substrates targeted by these complexes. Answering these questions will position investigators to translate this information into new therapies for patients.
- The lab has discovered an E3 ubiquitin ligase that regulates cytokine signaling in T cells. Mice develop asthma in the absence of this ligase. The Oliver Lab is working to determine how this ligase protects against T cell-mediated lung inflammation.
- The team identified a ligase required for the expansion of T cells following activation. In the absence of this ligase, T cells fail to mount protective immune responses.
- After identifying a ligase that regulates germinal center B cell responses, the Oliver Lab is working to determine how this ligase prevents autoreactive B cells from becoming long-lived plasma cells.