Using reporters of different misfolded proteins reveals differential strategies in processing protein aggregates.

Schneider KL, Ahmadpour D, Keuenhof KS, Eisele-Bürger AM, Berglund LL, Eisele F, Babazadeh R, Höög JL, Nyström T, Widlund PO

J. Biol. Chem. 298 (11) 102476 [2022-11-00; online 2022-09-09]

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.

Integrated Microscopy Technologies Gothenburg [Service]

PubMed 36096201

DOI 10.1016/j.jbc.2022.102476

Crossref 10.1016/j.jbc.2022.102476

pmc: PMC9636550
pii: S0021-9258(22)00919-X