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Endocytosis machinery is involved in aggregation of proteins with expanded polyglutamine domains
Author(s) -
Meriin Anatoli B.,
Zhang XiaoQian,
Alexandrov Ilya M.,
Salnikova Alexandra B.,
TerAvanesian Michael D.,
Chernoff Yury O.,
Sherman Michael Y.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6878com
Subject(s) - endocytic cycle , microbiology and biotechnology , protein aggregation , endocytosis , chemistry , actin , cytosol , yeast , biology , cell , biochemistry , enzyme
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) Slal, Sla2, and Panl were seen as clusters in the polyglutamine aggregates. These proteins associate with EC at the later stages of its maturation. In contrast, Edel and Entl, 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 polypep‐tides with polyglutamine domains in both yeast and mammalian cells.—Meriin A. B., Zhang, X., Alexan‐drov 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. FASEB J. 21, 1915–1925 (2007)