PubMed: 24706768

Protein aggregation can inhibit clathrin-mediated endocytosis by chaperone competition.
Proceedings of the National Academy of Sciences of the United States of America
Shah B | Lo DC | Yu A | Shibata Y | Calamini B | Morimoto RI

Evidence 1da96455fc

However, CME was substantially reduced in cells con- taining Q82 aggregates (Fig. 1 B , arrows), with quantification of internalized transferrin fluorescence showing a 63 ± 11% reduction in aggregate-containing cells compared with cells expressing soluble Q19 or Q82 (Fig. 1 C ).

Evidence d91d0823aa

CME inhibition was also observed in cells containing aggregated forms of polyQ- expanded Htt exon 1 (Htt Q53); these cells exhibited 50 ± 15% reduced levels of internalized transferrin compared with cells with soluble Htt Q23 or Htt Q53 protein (Fig. S2 A–C ).

Evidence 96c62d7944

In contrast, there was a marked reduction in CME in neurons containing mutant Htt exon 1 Q73-CFP aggregates compared with nonexpressing cells (Fig. 5 B , Center ; quantification in Fig. 5 D );

Evidence d5f650ef25

It has been proposed that such an imbalance may trigger the onset of many neurodegenerative diseases (10, 26), and recent studies report that polyglutamine (polyQ)-based aggregates can se- quester and inhibit the function of a low-abundance cochaper- one, Sis1p/DNAJB1, in protein degradation (27).

Evidence 8c829248c2

Previous studies have shown that ag- gregation of expanded polyQ negatively affects endocytosis in yeast and in human HEK 293 cells (34).

Evidence ab4c41ee12

Nevertheless, HSC70-ag- gregate colocalization reliably predicted CME inhibition.

Evidence faf9e56c42

Importantly, aggregate-driven CME inhibition is reversible and can be rescued by nominally increasing HSC70 levels.

Evidence 703c5ef3a1

Although internalized transferrin levels remained un- changed in cells with near-normal amounts of HSC70, cells with over a 50% reduction in HSC70 expression had significant CME inhibition (compare Fig. 2 E and D ), with a 51 ± 17% decrease in internalized transferrin fluorescence compared with nondepleted cells.

Evidence cbe0288e24

. Be- yond maintaining the general solubility of the CME machinery, HSC70 is specifically required for both the disassembly of the clathrin coat from endocytosed vesicles (20, 29 – 31) and in the recycling of coat components back to the plasma membrane.

Evidence 11c0371016

Down- regulation of CME was not limited to polyQ-induced aggre- gation; cells with aggregated mutant SOD1 A4V also exhibited a 50 ± 10% decrease in levels of internalized transferrin com- pared with cells expressing the soluble WT or mutant protein (Fig. 1 E–G ).

Evidence 58cd56252b

Here, we show that diverse disease-associated aggregates se- quester the highly abundant major chaperone heat shock cognate protein 70 (HSC70) to the point of functional collapse of an essential cellular process, clathrin-mediated endocytosis (CME).


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