HSP90 cleavage associates with oxidized proteins accumulation after oxidative stress

Oxidative stress, OS, has been associated to a variety of phenomena as cancer progression, neurodegeneration and ageing itself. At a molecular level, OS leads to protein carbonylation, a non-enzymatic irreversible event and common feature of aged cells. Carbonylated proteins are dysfunctional and can accumulate, in the form of protein aggregates that alter cellular functionality. To cope with carbonylated proteins, cells employ the proteasome, the main non-lysosomal structure for carbonylated proteins turnover. However, if the degrading rate is inferior to carbonylated proteins formation rate, protein aggregates form. In a previous study, in oxidative stress challenged Jurkat cells we could verify that cytoplasmatic actin becomes heavily carbonylated and forms oxidized actin aggregates, which lead to proliferation impairment and proteasome activity diminishment, similar to senescence like states. Because under these oxidative conditions there is a proteostasis disturbance, such as oxidized proteins (especially actin) accumulation and proteasome activity impairment, Hsp90 involvement was studied. Hsp90, a molecular chaperone, assists oxidized proteins degradation and also protects the 20S proteasome from oxidative inactivation. We reasoned that the mechanism by which protein aggregates can form, mainly happens due to Hsp90 lesser functionality, which we attribute to cleavage. In our study, we were able to verify that cleaved Hsp90 is present in protein aggregates and that it occurs before actin insolubilization, verified after fractioning soluble and insoluble cellular extracts. We are convinced, supported by our data, that cleaved Hsp90 is an important intervenient for oxidized protein accumulation and proteasome inactivation. However, further studies should follow to confirm our hypothesis.