Research Abstract:
Research in the Hanson laboratory focuses on fundamental unknowns of intracellular membrane organization and trafficking, with a special interest in their regulation by a family of chaperone-like ATPases known as AAA+ (ATPases associated with a variety of cellular activities) proteins. Several AAA+ proteins – including NSF, p97/VCP, VPS4/SKD1, and torsinA – play critical roles in regulating the assembly and disassembly of protein complexes that mediate such events as membrane fusion and multivesicular body biogenesis. We use a range of cell biological and biochemical tools to study the pathways in which these enzymes are involved, and to explore how derangements in these pathways lead to disease.
Mechanisms of multivesicular body biogenesis: The endosomal system internalizes membrane and protein from the plasma membrane, and then in a topologically distinct process internalizes membrane into itself to form multivesicular bodies (MVBs). This process is critical for downregulation and degradation of signaling receptors from the plasma membrane as well as many other membrane components. We are studying the AAA+ ATPase VPS4 and its ESCRT protein substrates in order to understand how assembly and disassembly of membrane associated complexes drive and regulate the formation of MVBs and the related processes of viral budding and cell abscission. This work will advance understanding of a poorly understood membrane transformation that is important to understanding many diseases, including cancer, dementia, and cataract formation.
TorsinA in the nuclear envelope: In a second project, we are studying a novel family of AAA+ proteins in the lumen of the endoplasmic reticulum and nuclear envelope. All are related to torsinA, the protein that is mutated in inherited DYT1 early onset torsion dystonia. We defined the nuclear envelope as a site of torsinA action within the ER, and are studying the remodeling reactions mediated by it (and other torsin family members) on interacting proteins in both the nuclear envelope and peripheral ER. Current work suggests that torsinA modulates components of the LINC complexes that bridge the nuclear envelope to connect nucleus to cytoskeleton.
Selected Publications:
Shim S, Merrill SA, Hanson PI. Novel interactions of ESCRT-III with LIP5 and VPS4 and their implications for ESCRT-III disassembly. Mol. Biol. Cell 2008 19:2661-2672.
Shim S, Kimpler LA, Hanson PI. Structure/function analysis of four core ESCRT-III proteins reveals common regulatory role for extreme C-terminal domain. Traffic 2007 8:1068-79.
Hanson PI, Roth R, Lin Y, Heuser JE. Plasma membrane deformation by circular arrays of ESCRT-III protein filaments. J Cell Biol. 2008 180: 389-402.
Kock N, Naismith TV, Boston HE, Ozelius LJ, Corey DP, Breakefield XO, Hanson PI. Effects of genetic variations in the dystonia protein torsinA: identification of polymorphism at residue 216 as protein modifier. Human Molecular Genetics 2006 15: 1355-64.
Hanson PI and Whiteheart SW. AAA+ proteins: have engine, will work. Nature Reviews Molecular Cell Biology 2005 6: 519-529.
Last Updated: 02/03/2009 |