TAU HOMEOSTASIS IS INFLUENCED BY PIAS4

SOKN, MARÍA CLARA; ATTORRESI, ALEJANDRA; LIBERMAN, ANA CLARA; GOBBINI, ROMINA PAULA; FALZONE, TOMÁS; VELARDO, VANINA GISELLE*; SENIN, SERGIO

Simposio; Estado actual y retos de las investigaciones en Latinoamérica de las enfermedades neurodegenerativas y epilepsia; 2022

La iniciativa cerebro latinoamericana (LATBrain)

Tauopathies are neurodegenerative diseases characterized by the de-regulation of tau homeostasis. Accumulating evidence points to an important role of the PIAS family SUMO ligases as regulators of several key proteins involved in neurodegeneration. This work aimed to determine the role of PIAS family in the regulation of tau protein homeostasis. By means of a western blot (WB)-based screening in HT22 cells overexpressing human 2N4R WT tau (hTau) together with the PIAS family members, we observed a robust increase in total tau levels triggered only by PIAS4. Importantly, the catalytically inactive (CA) ligase PIAS4CA was incapable of modulating tau, suggesting that PIAS4 mediated SUMOylation is involved in tau deregulation. Besides, Tau-BifC assay showed that PIAS4 enhances tau dimerization, a process that has been linked to tau pathological deregulation. PIAS4 effect on tau was corroborated in N2a cells stably expressing similar to endogenous levels of WT hTau or the SUMOylation mutant tau (hTauK340R). On one hand, PIAS4 promoted not only WT hTau but also hTauK340R accumulation, suggesting that the enzyme activity on tau does not involve direct tau SUMOylation. On the other hand, PIAS4 silencing markedly decreased total tau protein levels. Finally, our autophagic flux assays revealed that PIAS4 overexpression inhibits autophagic activity whereas PIAS4 silencing promotes it. We propose that PIAS4 is an autophagy modulator that regulates tau clearance.