Research Overview

The nuclear envelope is a complex and highly dynamic structure that is also a hot spot for human diseases collectively known as nuclear envelopathies. Research in our laboratory focuses on furthering our understanding of nuclear protein quality control, transport of large cargo across the nuclear membranes, and the relationship between nuclear membrane proteins and human disease.

Torsin ATPase structure and function in relation to primary dystonia

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.

Torsin ATPases are the only known members of the AAA+ ATPase superfamily that reside inside the endoplasmic reticulum and perinuclear space. The key pathological hallmark of Torsin-deficient animal models is an accumulation of vesicular intermediates in the nuclear envelope of neurons; however the precise cellular function of these essential ATPases remains poorly understood. Studying Torsin ATPases has significant medical relevance because a mutation in TorsinA is responsible for a congenital (DYT1) form of Dystonia, a group of highly debilitating movement disorders that are more prevalent than Amyotrophic Lateral Sclerosis (A.L.S), Huntington’s disease, and muscular dystrophy combined.

 

Our laboratory was the first to establish a functional in vitro system to study Torsin ATPases, and we have since made a number of exciting and unexpected discoveries. We demonstrated that Torsin ATPases are outliers of the AAA+ superfamily of ATPases in the human genome in that they lack significant basal ATPase activity and that their catalytic activity is strictly reliant on LAP1 and LULL1, two accessory cofactors that accelerate the hydrolysis step by several orders of magnitude (P.N.A.S. 110(17):E1545-54) by virtue of an active site complementation mechanism (P.N.A.S. 111(45):E4822-3). Importantly, we found that this activation mechanism is offset by disease-causing mutations, which is the first direct demonstration of a loss-of-function mechanism for DYT1 Dystonia (see NSMB 121(12):1025-7 for a News&Views article on our paper by McCullough and Sundquist).

 

Current research in our laboratory is focused on characterizing the structure of the Torsin-cofactor complex in the natural context of the membrane, examining the specific cellular and mechanistic roles of various types of Torsin-cofactor complexes, and examining the function of Torsin ATPases in the transport of large cargo out of the nucleus via membrane budding. We pursue these goals in interdisciplinary fashion, using cell biological, biochemical, and structural/biophysical approaches.

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.