Controlling Protein Compartmentalization to Overcome Disease

Abstract

Over the past decade, considerable progress has been made to improve our understanding of the intracellular transport of proteins. Mechanisms of nuclear import and export involving classical receptors have been studied. Signal sequences required for directing a protein molecule to a specific cellular compartment have been defined. Knowledge of subcellular trafficking of proteins has also increased our understanding of diseases caused due to mislocalization of proteins. A specific protein on deviating from its native cellular compartment may result in disease due to loss of its normal functioning and aberrant activity in the "wrong" compartment. Mislocalization of proteins results in diseases that range from metabolic disorders to cancer. In this review we discuss some of the diseases caused due to mislocalization. We further focus on application of nucleocytoplasmic transport to drug delivery. Various rationales to treat diseases by exploiting intracellular transport machinery have been proposed. Although the pathways for intracellular movement of proteins have been defined, these have not been adequately utilized for management of diseases involving mislocalized proteins. This review stresses the need for designing drug delivery systems utilizing these mechanisms as this area is least exploited but offers great potential.

Protein localization in disease and therapy

“…Several general regulators of the nuclear import process, including the NPC, the transport receptors and the import partners have also been proposed as targets for therapeutic intervention (Chahine and Pierce, 2009;Davis et al, 2007). Monoclonal antibodies directed against the FG-repeats of nucleoporins, which are thought to mediate the sequential binding of nuclear import receptors during the translocation, have been used successfully in rat liver nuclear envelopes to prevent cargo association with the NPC and block the translocation of proteins (Gasiorowski and Dean, 2003;Snow et al, 1987).…”

“…However, this has not yet been extensively explored (Davis et al, 2007). In fact, there is currently no small-molecule compound available to interfere with the nuclear import of proteins, but insight into the process of nuclear protein import has provided promising anticancer, antiviral and anti-inflammatory strategies (Faustino et al, 2007).…”

MAPK- Kinases as Nucleo-Cytoplasmic Shuttles for PPARγ

“…Deficiencies and alterations in these control mechanisms may contribute to aberrant signaling and gene expression leading to disease conditions such as inflammation and cancer. 1 Although the nuclear receptor superfamily (NR) was named after their member's prominent nuclear localization and genomic function, evidence accumulates to support their extra-nuclear localization and nongenomic actions. 2,3 Dynamic changes in subcellular localization of NRs upon stimulation with ligands exert important signaling roles for the NRs in different compartments.…”

Signal Sequences for Targeting of Gene Therapy Products to Subcellular Compartments: The Role Of CRM1 in Nucleocytoplasmic Shuttling of the Protein Switch

“…Besides the nucleus and cytoplasm, other subcellular compartments can be targeted as well via conserved amino acid sequences or motifs (for a review, see (11)). Proteins can also be targeted to the nucleolus (12) via a RRRANNRRR motif; the mitochondria via an amino acid amphipathic alpha helix with positive residues clustered on one side, and polar residues clustered on the other side (13,14); the trans-golgi network (15) via a signal consisting of a di-leucine motif followed by two acidic clusters; lysosomes and endosomes (16) via tyrosine-based sorting signals that conform to the NPXY or YXX consensus motifs or di-leucine-based [DE]XXXL[LI] and DXXLL consensus motifs; peroxisomes via the SKL signal sequence at the C-terminus (13); the endoplasmic reticulum via the well-known KDEL endoplasmic retention signal (17,18) and others.…”