Research Overview

Defects in protein folding have been identified as underlying cause for a steadily increasing number of congenital diseases, yet the connection between protein misfolding and disease remains poorly understood. We study how a cell decides whether a protein is repaired or must be degraded, and how this decision is relayed to the transport and degradation machinery.

Nuclear envelopathies and viral assembly

Funding

These projects are funded through an NIH Director's New Innovator Award and a New Scholar in Aging Award by the Ellison Medical Foundation.

Nuclear envelopathies are a diverse group of congenital diseases that are caused by mutations affecting proteins in the nuclear envelope or lamina. We hypothesize that envelopathy-associated alleles act at least in part through proteotoxicity, i.e. by a gain of function mechanism that leads to a poisoning of the protein quality control system. How proteins in the nuclear periphery are turned over or repaired is largely unknown, and the mechanisms that serve to remove nuclear protein aggregates are equally elusive. Our goal is to unravel the cellular mechanisms that regulate protein homeostasis in the nuclear periphery, and to elucidate the role that these pathways play in muscular dystrophies, premature aging and related envelopathies. We exploit viral proteins known to manipulate the nuclear envelope as a novel approach to identify cellular factors involved in protein turnover and aggregate removal from the nucleus.

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Ubiquitin, deubiquitinating enzymes, and inter-compartmental substrate flux

Funding

These projects are funded through an NIH Director's New Innovator Award and a New Scholar in Aging Award by the Ellison Medical Foundation.

In higher eukaryotes, the ubiquitin / proteasome system and the lysosome cooperate to dispose of defective proteins. We apply a combination of structural, biochemical and cell biological approaches to dissect the multiple roles of ubiquitin in protein quality control. One of our immediate goals is to decipher the largely enigmatic role of deubiquitinating enzymes, which counterbalance the activity of ubiquitin ligases. Our long-term goal is to understand why and how misfolded proteins are partitioned between cellular compartments, and to dissect how individual branches of the protein quality control network are wired to form a robust network.

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