Location, location, location: altered transcription factor trafficking in neurodegeneration

Abstract

Neurons may be particularly sensitive to disruptions in transcription factor trafficking. Survival and injury signals must traverse dendrites or axons, in addition to soma, to affect nuclear transcriptional responses. Transcription factors exhibit continued nucleocytoplasmic shuttling; the predominant localization is regulated by binding to anchoring proteins that mask nuclear localization/export signals and/or target the factor for degradation. Two functional groups of karyopherins, importins and exportins, mediate RanGTPase-dependent transport through the nuclear pore. A growing number of recent studies, in Alzheimer, Parkinson, and Lewy body diseases, amyotrophic lateral sclerosis, and human immunodeficiency virus encephalitis, implicate aberrant cytoplasmic localization of transcription factors and their regulatory kinases in degenerating neurons. Potential mechanisms include impaired nuclear import, enhanced export, suppression of degradation, and sequestration in protein aggregates or organelles and may reflect unmasking of alternative cytoplasmic functions, both physiologic and pathologic. Some "nuclear" factors also function in mitochondria, and importins are also involved in axonal protein trafficking. Detrimental consequences of a decreased nuclear to cytoplasmic balance include suppression of neuroprotective transcription mediated by cAMP- and electrophile/antioxidant-response elements and gain of toxic cytoplasmic effects. Studying the pathophysiologic mechanisms regulating transcription factor localization should facilitate strategies to bypass deficits and restore adaptive neuroprotective transcriptional responses.

FIGURE 1

(A) Schematic diagram of a generalized signal transduction pathway resulting in activation and nuclear import of a transcription factor and subsequent transcriptional activation. Under resting conditions (1), the transcription factor is bound to a cytoplasmic anchoring protein. Receptor ligation and/or physiologic redox signals result in phosphorylation of the transcription factor and/or phosphorylation or oxidation of the anchor and release of the transcription factor (2). The exposed nuclear localization signal (NLS) is recognized by importins, which escort the transcription factor into the nucleus (3). Importin β is also involved in retrograde transport of activated signaling proteins along neuritic processes (4). Within the nucleus, RanGTP binds importin β, which promotes disassembly of the import complex (5), freeing the transcription factor to bind DNA and form active transcription regulatory complexes. Transcription may be terminated by nuclear phosphatases and/or proteasomal degradation (6). Nuclear export is mediated by complexes consisting of cargo, an exportin, and RanGTP. Near the cytoplasmic face of the nuclear envelope, Ran GTPase-activating protein (RanGAP) maintains the nuclear-to-cytoplasmic RanGTP gradient by catalyzing GTP hydrolysis (7), promoting disassembly of the export complex. Importins are also recycled to the cytoplasm through a RanGTP-mediated mechanism. (B) Proposed mechanisms through which oxidative stress could impair nuclear transport of transcription factors, depriving the cell of adaptive, prosurvival transcriptional support and eliciting potentially detrimental cytosolic effects. Under conditions of oxidative stress such as those that occur during acute and chronic neurodegenerative insults, adaptive signaling pathways are activated by phosphorylation and/or redox mechanisms. However, post-translational modifications may impair cargo recognition by importins (1). Oxidative cross-linking of proteins, the presence of mutant neurodegenerative disease-associated proteins, and/or oxidative inactivation of phosphatase or proteasomal function could promote protein aggregation, resulting in further sequestration of signaling proteins (2). Sustained cytoplasmic signaling and/or organelle-targeted activation could further contribute to pathogenic mechanisms, such as calpain activation, altered mitochondrial function or autophagic stress from dysregulated autophagy (3). Alternatively, the nuclear pore complex itself could be the target of oxidative damage, with impairment of import and/or leakage of proteins from the nucleus (4). Intranuclear aggregation or other post-translational or oxidative/nitrosative modifications may further interfere with proper transcriptional responses (5), resulting in loss of stabilizing transcription complex-DNA interactions. Dissipation of the RanGTP gradient and/or impairment of importin recycling could also affect nuclear trafficking (6). Finally, lack of transcriptional support and/or oxidative or aggregative damage to axons and dendrites could result in further impairment in transmission of signals needed for maintenance and/or repair of neurites and synaptic structures (7). ROS, reactive oxygen species.