NR APJX
AU Meriin,A.B.; Zhang,X.; Miliaras,N.B.; Kazantsev,A.; Chernoff,Y.O.; McCaffery,J.M.; Wendland,B.; Sherman,M.Y.
TI Aggregation of expanded polyglutamine domain in yeast leads to defects in endocytosis
QU Molecular and Cellular Biology 2003 Nov; 23(21): 7554-65
PT journal article
AB The role of aggregation of abnormal proteins in cellular toxicity is of general importance for understanding many neurological disorders. Here, using a yeast model, we demonstrate that mutations in many proteins involved in endocytosis and actin function dramatically enhance the toxic effect of polypeptides with an expanded polyglutamine (polyQ) domain. This enhanced cytotoxicity required polyQ aggregation and was dependent on the yeast protein Rnq1 in its prion form. In wild-type cells, expression of expanded polyQ followed by its aggregation led to specific and acute inhibition of endocytosis, which preceded growth inhibition. Some components of the endocytic machinery were efficiently recruited into the polyQ aggregates. Furthermore, in cells with polyQ aggregates, cortical actin patches were delocalized and actin was recruited into the polyQ aggregates. Aggregation of polyQ in mammalian HEK293 cells also led to defects in endocytosis. Therefore, it appears that inhibition of endocytosis is a direct consequence of polyQ aggregation and could significantly contribute to cytotoxicity.
MH Actins/metabolism; Animals; Cell Fractionation; Cell Line; Cell Survival; Endocytosis/*physiology; Fungal Proteins/genetics/*metabolism; Genes, Fungal; Human; Lipids/metabolism; Mutation; Peptides/*metabolism; Prions/metabolism; Protein Structure, Tertiary; Receptors, Transferrin/metabolism; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.; Yeasts/physiology/ultrastructure
AD Department of Biochemistry, Boston University School of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
SP englisch
PO USA