RESEARCH
How does the ubiquitin system regulate organelle communication?
It is now well established that organelles interact with one another by association of proteins on each organelle. This interaction created a membrane contact site (MCS) that allows organelles to communicate with one another to regulate a number of physiologically relevant events such as calcium transfer and lipid synthesis. We have recetly identified a role for the p97 AAA-ATPase and its ER tethered adaptor UBXD8 in regulating the association of the ER and mitochondria to regulate MCS by modulating membrane lipid saturation.
We are interested in identifying new MCS tethers using proximity based spatial protemics.
We are interested in identifying new MCS tethers using proximity based spatial protemics.
COS7 cells expressing mito-BFP (mitochondria) Sec61-GFP (ER) and mCherry UBXD8. UBXD8 accumulates at ER- mitochondria MCS
Understanding how defects in proteostasis cause degenerative human diseases
We are particularly fascinated by how p97 mutations cause neurodegeneration and myopathy. These disorders are characterized by inclusion bodies and rimmed vacuoles containing ubiquitinated aggregates suggestive of deficits in both the ubiquitin system and autophagy.
However, we do not yet have a full understanding of how the numerous mutations globally impact p97-dependent processes. Understanding p97 function within the cell will allow us to appreciate how this multi-functional enzyme orchestrates the triaging of unwanted proteins and how this process goes awry in protein aggregate disorders.
We have developed induced pluripotent stem cells harboring p97 disease mutations to study the impact of p97 mis-regulation in cells such as motor neurons and myocytes.
However, we do not yet have a full understanding of how the numerous mutations globally impact p97-dependent processes. Understanding p97 function within the cell will allow us to appreciate how this multi-functional enzyme orchestrates the triaging of unwanted proteins and how this process goes awry in protein aggregate disorders.
We have developed induced pluripotent stem cells harboring p97 disease mutations to study the impact of p97 mis-regulation in cells such as motor neurons and myocytes.
Motor neurons stained with Tuj1
Global Proteomic Profiling of p97 cellular targets
While we appreciate the importance of p97 in many cellular pathways, we have little knowledge of the substrates it targets with in those pathways. Our goal is to identify substrates that rely on distinct p97 adaptor modules and determine if and how these p97-adaptor-substrate complexes are mis-regulated in human disorders such as ALS and IBMPFD.
We have developed a panel of individual adaptor knockout cell lines using CRISPR gene editing that we are using in quantitative proteomic studies to understand how cells respond to loss of a specific p97 adaptor.
We have developed a panel of individual adaptor knockout cell lines using CRISPR gene editing that we are using in quantitative proteomic studies to understand how cells respond to loss of a specific p97 adaptor.