High-mobility group box 1 links sensing of reactive oxygen species by huntingtin to its nuclear entry.

Huntington's disease (HD) is a neurodegenerative, age-onset disorder caused by a CAG DNA expansion in exon 1 of the gene, resulting in a polyglutamine expansion in the huntingtin protein. Nuclear accumulation of mutant huntingtin is a hallmark of HD, resulting in elevated mutant huntingtin levels in cell nuclei. Huntingtin is normally retained at the endoplasmic reticulum via its N17 amphipathic α-helix domain but is released by oxidation of Met-8 during reactive oxygen species (ROS) stress.

Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin.

Huntington disease (HD) is a neurodegenerative disorder caused by a CAG expansion within the huntingtin gene that encodes a polymorphic glutamine tract at the amino terminus of the huntingtin protein. HD is one of nine polyglutamine expansion diseases. The clinical threshold of polyglutamine expansion for HD is near 37 repeats, but the mechanism of this pathogenic length is poorly understood.

A multifunctional, multi-pathway intracellular localization signal in Huntingtin.

Nuclear accumulation of the polyglutamine-expanded mutant huntingtin protein remains one of the most predictive cell biological phenotypes of Huntington's disease (HD) progression in patient brain samples and mouse models of the disease. Yet, the relationship between huntingtin nuclear import, neuronal dysfunction and toxicity is not fully understood and it remains unclear whether nuclear accumulation is required for disease onset. Here, we discuss several studies that have guided current understanding of this subject, and highlight our recent data detailing the discovery of a karyopherin β1/β2-type nuclear localization signal near the N-terminus of huntingtin.

Identification of a karyopherin β1/β2 proline-tyrosine nuclear localization signal in huntingtin protein.

Among the known pathways of protein nuclear import, the karyopherin β2/transportin pathway is only the second to have a defined nuclear localization signal (NLS) consensus. Huntingtin, a 350-kDa protein, has defined roles in the nucleus, as well as a CRM1/exportin-dependent nuclear export signal; however, the NLS and exact pathway of import have remained elusive. Here, using a live cell assay and affinity chromatography, we show that huntingtin has a karyopherin β2-dependent proline-tyrosine (PY)-NLS in the amino terminus of the protein.

Cofilin nuclear-cytoplasmic shuttling affects cofilin-actin rod formation during stress.

Cofilin protein is involved in regulating the actin cytoskeleton during typical steady state conditions, as well as during cell stress conditions where cofilin saturates F-actin, forming cofilin-actin rods. Cofilin can enter the nucleus through an active nuclear localization signal (NLS), accumulating in nuclear actin rods during stress. Here, we characterize the active nuclear export of cofilin through a leptomycin-B-sensitive, CRM1-dependent, nuclear export signal (NES).

Kinase inhibitors modulate huntingtin cell localization and toxicity.

Two serine residues within the first 17 amino acid residues of huntingtin (N17) are crucial for modulation of mutant huntingtin toxicity in cell and mouse genetic models of Huntington's disease. Here we show that the stress-dependent phosphorylation of huntingtin at Ser13 and Ser16 affects N17 conformation and targets full-length huntingtin to chromatin-dependent subregions of the nucleus, the mitotic spindle and cleavage furrow during cell division. Polyglutamine-expanded mutant huntingtin is hypophosphorylated in N17 in both homozygous and heterozygous cell contexts.

Huntington's disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases.

After the successful cloning of the first gene for a polyglutamine disease in 1991, the expanded polyglutamine tract in the nine polyglutamine disease proteins became an obvious therapeutic target. Early hypotheses were that misfolded, precipitated protein could be a universal pathogenic mechanism. However, new data are accumulating on Huntington's disease and other polyglutamine diseases that appear to contradict the toxic aggregate hypothesis.