Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways.
Spinocerebellar ataxia type 2 is an inherited neurodegenerative disorder that is caused by an expanded trinucleotide repeat in the SCA2 gene, encoding a polyglutamine stretch in the gene product ataxin-2. Although evidence has been provided that ataxin-2 is involved in RNA metabolism, the physiological function of ataxin-2 remains unclear. Here, we demonstrate that ataxin-2 interacts with two members of the endophilin family, endophilin-A1 and endophilin-A3. To elucidate the physiological implications of these interactions, we exploited yeast as a model system and discovered that expression of ataxin-2 as well as both endophilin proteins is toxic for yeast lacking the SAC6 gene product fimbrin, a protein involved in actin filament organization and endocytotic processes. Intriguingly, expression of huntingtin, another polyglutamine protein interacting with endophilin-A3, was also toxic in Deltasac6 yeast. These effects can be suppressed by simultaneous expression of one of the two human fimbrin orthologs, L- or T-plastin. Moreover, we have discovered that ataxin-2 associates with L- and T-plastin and that overexpression of ataxin-2 leads to accumulation of T-plastin in mammalian cells. Thus, our findings suggest an interplay between ataxin-2, endophilin proteins and huntingtin in plastin-associated cellular pathways.
Ralser
Markus
M
Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.
Nonhoff
Ute
U
Albrecht
Mario
M
Lengauer
Thomas
T
Wanker
Erich E
EE
Lehrach
Hans
H
Krobitsch
Sylvia
S
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000067528:Ataxins; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry; D005260:Female; D017353:Gene Deletion; D006801:Humans; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D020754:Spinocerebellar Ataxias / Q000378:metabolism; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D018909:src Homology Domains / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D000067528:Ataxins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C105159:SH3GL1 protein, human; C107640:SH3GL2 protein, human; C026742:plastin