Using reporters of different misfolded proteins reveals differential strategies in processing protein aggregates
Artikel i vetenskaplig tidskrift, 2022

The accumulation of misfolded proteins is a hallmark of aging and many neurodegenerative diseases, making it important to understand how the cellular machinery recognizes and processes such proteins. A key question in this respect is whether misfolded proteins are handled in a similar way regardless of their genetic origin. To approach this question, we compared how three different misfolded proteins, guk1-7, gus1-3, and pro3-1, are handled by the cell. We show that all three are nontoxic, even though highly overexpressed, highlighting their usefulness in analyzing the cellular response to misfolding in the absence of severe stress. We found significant differences between the aggregation and disaggregation behavior of the misfolded proteins. Specifically, gus1-3 formed some aggregates that did not efficiently recruit the protein disaggregase Hsp104 and did not colocalize with the other misfolded reporter proteins. Strikingly, while all three misfolded proteins generally coaggregated and colocalized to specific sites in the cell, disaggregation was notably different; the rate of aggregate clearance of pro3-1 was faster than that of the other misfolded proteins, and its clearance rate was not hindered when pro3-1 colocalized with a slowly resolved misfolded protein. Finally, we observed using super-resolution light microscopy as well as immunogold labeling EM in which both showed an even distribution of the different misfolded proteins within an inclusion, suggesting that misfolding characteristics and remodeling, rather than spatial compartmentalization, allows for differential clearance of these misfolding reporters residing in the same inclusion. Taken together, our results highlight how properties of misfolded proteins can significantly affect processing.

protein aggregation

heat shock

chaperone

Saccharomyces cerevisiae

protein misfolding

proteostasis

yeast

spatial protein quality control

Författare

Kara L. Schneider

Göteborgs universitet

Doryaneh Ahmadpour

Göteborgs universitet

Chalmers, Biologi och bioteknik, Kemisk biologi

Katharina S. Keuenhof

Göteborgs universitet

Anna Maria Eisele-Bürger

Göteborgs universitet

Sveriges lantbruksuniversitet (SLU)

Lisa Larsson Berglund

Göteborgs universitet

Frederik Eisele

Göteborgs universitet

Roja Babazadeh

Göteborgs universitet

Johanna L. Höög

Göteborgs universitet

Thomas Nyström

Göteborgs universitet

Per O. Widlund

Göteborgs universitet

Journal of Biological Chemistry

0021-9258 (ISSN) 1083-351X (eISSN)

Vol. 298 11 102476

Ämneskategorier

Biokemi och molekylärbiologi

Biofysik

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

DOI

10.1016/j.jbc.2022.102476

PubMed

36096201

Mer information

Senast uppdaterat

2022-11-11