A5063733583- Endoplasmic Reticulum Stress and Disease
- Cellular transport and secretion
- Autophagy in Disease and Therapy
- Heat shock proteins research
- Pancreatic function and diabetes
- Fungal and yeast genetics research
- Erythrocyte Function and Pathophysiology
- Ubiquitin and proteasome pathways
- Lysosomal Storage Disorders Research
- RNA and protein synthesis mechanisms
- Lipid Membrane Structure and Behavior
- Calcium signaling and nucleotide metabolism
- Retinal Development and Disorders
- Ion Transport and Channel Regulation
- Ion channel regulation and function
- Protein Structure and Dynamics
- Genetic and Kidney Cyst Diseases
- Heart Failure Treatment and Management
- ATP Synthase and ATPases Research
- Immune Response and Inflammation
- Protist diversity and phylogeny
- Machine Learning in Bioinformatics
- Cell Adhesion Molecules Research
- Microtubule and mitosis dynamics
- Vibrio bacteria research studies
University of Pittsburgh
2013-2024
Rice University
2013
Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like 4 (TLR4). There has thus been great interest in discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, structure bound inhibitor E5564 was solved, raising possibility that novel target E5564-binding domain could designed. We utilized a similarity search algorithm conjunction with limited screening approach small molecule libraries...
Accumulation of misfolded proteins in cellular compartments can result stress-induced cell death. In the endoplasmic reticulum (ER), ER-associated degradation clears aberrant from secretory pathway. cytoplasm and nucleus, this job is left to cytoplasmic quality control (CytoQC) machinery. Both processes utilize chaperones ubiquitin-proteasome system aid protein elimination. Previous studies yeast have drawn comparisons between these using data structurally topologically different substrates....
The lysosomal storage disorder mucolipidosis type IV (MLIV) is caused by mutations in the transient receptor potential–mucolipin-1 (TRP-ML1) ion channel. “biogenesis” model for MLIV pathogenesis suggests that TRP-ML1 modulates postendocytic delivery to lysosomes regulating interactions between late endosomes and lysosomes. This based on observed lipid trafficking delays patient fibroblasts. Because membrane traffic aberrations may be secondary buildup chronically TRP-ML1–deficient cells, we...
Misfolding and aggregation of α-synuclein (α-syn) is associated with the development a number neurodegenerative diseases including Parkinson's disease (PD). Analyses post mortem tissues revealed presence molecular chaperones within α-syn aggregates, suggesting that play role in misfolding aggregation. In fact, inhibition chaperone activity aggravates toxicity, overexpression chaperones, particularly 70-kDa heat shock protein (Hsp70), protects against α-syn-induced toxicity. this study, we...
Significance Protein chaperone networks maintain homeostasis during cellular stress. Oncogenic transformation induces stress through increased demands on protein synthesis and folding. Thus, many cancer cells depend proteostasis for optimal growth. However, the subtype-specific roles of individual chaperones are incompletely understood. Through a chemical–genetic approach, we discovered an exquisite dependence rhabdomyosarcoma (RMS) cytosolic heat-shock 70 kDa (HSP70). HSP70 inhibition...
Wiskott-Aldrich syndrome protein (WASP) and WAVE stimulate actin-related (Arp)2/3-mediated actin polymerization, leading to diverse downstream effects, including the formation remodeling of cell surface protrusions, modulation migration, intracytoplasmic propulsion organelles pathogens. Selective inhibitors individual Arp2/3 activators would enable more exact dissection WASP- WAVE-dependent cellular pathways are potential therapeutic targets for viral pathogenesis. Wiskostatin is a recently...
The X-linked disorder Lowe syndrome arises from mutations in OCRL1, a lipid phosphatase that hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP 2 ). Most patients with develop proteinuria very early life. PIP dynamics are known to modulate numerous steps membrane trafficking, and it has been proposed OCRL1 activity regulates the biogenesis or trafficking of multiligand receptor megalin. To examine this possibility, we investigated effects siRNA-mediated knockdown on biosynthetic...
Integral membrane proteins fold inefficiently and are susceptible to turnover via the endoplasmic reticulum-associated degradation (ERAD) pathway. During ERAD, misfolded recognized by molecular chaperones, polyubiquitinated, retrotranslocated cytoplasm for proteasomal degradation. Although many aspects of this pathway defined, how transmembrane helices (TMHs) removed from into before is poorly understood. In study, we asked whether hydrophobic character a TMH acts as an energetic barrier...
Protein quality control (PQC) is required to ensure cellular health. PQC recognized for targeting the destruction of defective polypeptides, whereas regulated protein degradation mechanisms modulate concentration specific proteins in concert with physiological demands. For example, ion channel levels are physiologically within tight limits, but a system-wide approach define which degradative systems involved lacking. We focus on Kir2.1 potassium because altered lead human disease and...
Sorting signals for apically destined proteins are highly diverse and can be present within the luminal, membrane-associated, cytoplasmic domains of these proteins. A subset apical partition into detergent-resistant membranes, association with glycolipid-enriched microdomains or lipid rafts may important their proper targeting. Recently, we observed that raft-associated raft-independent take different routes to surface polarized Madin-Darby canine kidney cells (Cresawn, K. O., Potter, B. A.,...
Cancer cells thrive when challenged with proteotoxic stress by inducing components of the protein folding, proteasome, autophagy and unfolded response (UPR) pathways. Consequently, specific molecular chaperones have been validated as targets for anti-cancer therapies. For example, inhibition Hsp70 family proteins (hereafter Hsp70) in rhabdomyosarcoma triggers UPR induction apoptosis. To define how these cancer respond to compromised proteostasis, we compared that were sensitive (RMS13) or...
Ubiquitination of ENaC subunits has been shown to negatively regulate the cell surface expression channels. We have previously demonstrated that epsin links ubiquitinated clathrin adaptors for clathrin-mediated endocytosis. Epsin is thought directly modify curvature membranes upon binding phosphatidylinositol 4,5-bisphosphate (PIP2) where it recruits and stimulates lattice assembly. Murine 4-phosphate 5-kinase alpha (PI5KIalpha) enhance endocytosis in a PIP2-dependent manner. tested...
Abstract Misfolded proteins in the endoplasmic reticulum (ER) are selected for ER‐associated degradation (ERAD). More than 60 disease‐associated substrates ERAD pathway due to presence of missense or nonsense mutations. In yeast, Hsp104 molecular chaperone disaggregates detergent‐insoluble substrates, but spectrum that may be aggregation prone is unknown. To determine if recognizes aggregation‐prone associated with human diseases, we developed yeast expression systems a hydrophobic...
Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at clathrin coated pits (CCPs) is crucial for the recruitment adaptors and other components internalization machinery, as well regulating actin dynamics during endocytosis. PtdIns(4,5)P2 synthesized from 4-phosphate by any three 5-kinase type I (PIP5KI) isoforms (α, β or γ). PIP5KIβ localizes almost exclusively to apical surface in polarized mouse cortical collecting duct cells, whereas have a less membrane...
To maintain secretory pathway fidelity, misfolded proteins are commonly retained in the endoplasmic reticulum (ER) and selected for ER-associated degradation (ERAD). Soluble use ER chaperones retention, but machinery that restricts aberrant membrane to is unclear. In fact, some escape traffic lysosome/vacuole. this end, we describe a model substrate, SZ∗, contains an export signal also targeted ERAD. We observe decreased retention when chaperone-dependent SZ∗ ubiquitination compromised....
Transmembrane proteins have unique requirements to fold and integrate into the endoplasmic reticulum (ER) membrane. Most notably, transmembrane must in three separate environments: extracellular domains oxidizing environment of ER lumen, (TMDs) within lipid bilayer, cytosolic reducing cytosol. Moreover, each region is acted upon by a set chaperones monitored components associated quality control machinery that identify misfolded compartment. One factor lumenal Hsp70-like chaperone, Lhs1. Our...
GRP170, a product of the
Polarized epithelial cells efficiently sort newly synthesized apical and basolateral proteins into distinct transport carriers that emerge from the trans-Golgi network (TGN), this sorting is recapitulated in nonpolarized cells. While targeting signals of basolaterally destined are generally cytoplasmically disposed, not typically accessible to cytosol, machinery required for segregation export cargo remains largely unknown. Here we investigated molecular requirements TGN marker influenza...