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Endocytosis machinery is involved in aggregation of proteins with expanded polyglutamine domains

Anatoli B. Meriin^*, XiaoQian Zhang^*, Ilya M. Alexandrov, Alexandra B. Salnikova, Michael D. Ter-Avanesian, Yury O. Chernoff and Michael Y. Sherman^*,1

^* Department of Biochemistry, Boston University Medical School, Boston, Massachusetts, USA;

School of Biology and Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; and

Cardiology Research Center, Moscow, Russia

¹Correspondence: 715 Albany St., K323, Boston, MA 02118, USA. E-mail: sherma1{at}bu.edu

The cell’s failure to refold or break down abnormal polypeptides often leads to their aggregation, which could cause toxicity and various pathologies. Here we investigated cellular factors involved in protein aggregation in yeast and mammalian cells using model polypeptides containing polyglutamine domains. In yeast, a number of mutations affecting the complex responsible for formation of the endocytic vesicle reduced the aggregation. Components of the endocytic complex (EC) Sla1, Sla2, and Pan1 were seen as clusters in the polyglutamine aggregates. These proteins associate with EC at the later stages of its maturation. In contrast, Ede1 and Ent1, the elements of EC at the earlier stages, were not found in the aggregates, suggesting that late ECs are involved in polyglutamine aggregation. Indeed, stabilization of the late complexes by inhibition of actin polymerization enhanced aggregation of polypeptides with polyglutamine domains. Similarly, in mammalian cells, inhibitors of actin polymerization, as well as depletion of a mediator of actin polymerization, Arp2, strongly enhanced the aggregation. In contrast, destabilization of EC by depletion or inhibition of a scaffolding protein N-WASP effectively suppressed the aggregation. Therefore, EC appears to play a pivotal role in aggregation of cytosolic polypeptides with polyglutamine domains in both yeast and mammalian cells.—Meriin, A. B., Zhang, X., Alexandrov, I. M., Salnikova, A. B., Ter-Avanesian, M. D., Chernoff, Y. O., Sherman, M. Y. Endocytosis machinery is involved in aggregation of proteins with expanded polyglutamine domains.

Key Words: Huntington’s disease

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