Protein localization in disease and therapy

Abstract

SummaryThe eukaryotic cell is organized into membrane-covered compartments that are characterized by specific sets of proteins and biochemically distinct cellular processes. The appropriate subcellular localization of proteins is crucial because it provides the physiological context for their function. In this Commentary, we give a brief overview of the different mechanisms that are involved in protein trafficking and describe how aberrant localization of proteins contributes to the pathogenesis of many human diseases, such as metabolic, cardiovascular and neurodegenerative diseases, as well as cancer. Accordingly, modifying the disease-related subcellular mislocalization of proteins might be an attractive means of therapeutic intervention. In particular, cellular processes that link protein folding and cell signaling, as well as nuclear import and export, to the subcellular localization of proteins have been proposed as targets for therapeutic intervention. We discuss the concepts involved in the therapeutic restoration of disrupted physiological protein localization and therapeutic mislocalization as a strategy to inactivate disease-causing proteins. Journal of Cell Sciencecompartment has been associated with human diseases, and in the following sections we will discuss some of the mechanisms that can lead to such changes in protein localization. Mislocalization through alterations of the protein trafficking machineryDysregulation of the protein trafficking machinery can have dramatic effects on general protein transport processes, modifying cell morphology and physiology. Along these lines, changes in the nuclear pore complex (NPC) have been linked to several genetic disorders (Chahine and Pierce, 2009). For example, in patients with familial atrial fibrillation, the homozygous mutation R391H in the nucleoporin NUP155 has been shown to reduce nuclear envelope permeability and affect the export of Hsp70 mRNA and import of HSP70 protein (Zhang et al., 2008). That study was the first to link a nucleoporin defect to cardiovascular disease.Mutations in other components of the NPC, such as the nucleoporin p62 protein and ALADIN (alacrima achalasia adrenal insufficiency neurologic disorder, officially known as AAAS) are thought to cause the neurodegenerative diseases infantile bilateral striatal necrosis and triple A syndrome, respectively (Basel-Vanagaite et al., 2006; Kiriyama et al., 2008). Mutant ALADIN prevents nuclear entry of the DNA repair proteins aprataxin and DNA ligase I and, therefore, results in increased DNA damage and subsequent cell death caused by oxidative stress (Kiriyama et al., 2008). In a similar fashion, protein import into other organelles can be affected by mutations in the trafficking machinery. For instance, mutations in the peroxin gene PEX7, which encodes a peroxisomal import receptor that is responsible for the transport of several essential peroxisomal enzymes, have been found to cause the peroxisome biogenesis disorder rhizomelic chondrodysplasia punctata type 1 (RCDP1) (Braverman e...

Molecular Pathways: Anticancer Activity by Inhibition of Nucleocytoplasmic Shuttling

“…Mislocalization of those molecules may alter their activities, thus disturbing the homeostasis of the cells and causing diseases such as cancer. Growing evidence suggests that dysregulation of nucleocytoplasmic shuttling is involved in promoting cancer cell survival, carcinogenesis, tumor progression, and drug resistance (6). Mislocalization of tumor suppressor proteins (TSP) appears to play a key role in cancer pathogenesis.…”

The cytosolic chaperone α-Crystallin B rescues appropriate folding and compartmentalization of misfolded multispan transmembrane proteins

“…Not surprisingly, a number of human hereditary pathologies are linked to the loss of function of mutated TMPs (receptor, channel, pump or transporter), which then fail to attain native configuration (Hartl et al, 2011;Hung and Link, 2011). In some cases, these folding mutations primarily affect the transport of the TMPs but do not completely abolish the biological activity; thus the rescue of their proper localization could, in itself, significantly ameliorate the pathological consequences (Coppinger et al, 2012;Hung and Link, 2011). Different categories of chaperone operate for TMPs, and the chaperone activity that is best characterized is of those located in the lumen of the ER (Braakman and Bulleid, 2011).…”

Synthetic physical interactions map kinetochore regulators and regions sensitive to constitutive Cdc14 localization

“…For example, protein relocation underpins most cell-signaling pathways (1) and the establishment of cell polarity and asymmetric cell division both require highly specialized relocation of proteins within the cell (2). Furthermore, the aberrant localization of proteins underlies the pathology of a number of diseases (3). However, our understanding of the effect of relocalizing members of the proteome is limited to specific studies typically concerning individual proteins, and only a select few studies have globally monitored protein relocation (4,5).…”