PIAS4 SUMO E3 ligase modulates tau and phospho-tau levels

SOKN, C.; GOBBINI, R.; BUDZIÑSKY, M.L.; SENIN, S.; ARZT, E.; LIBERMAN, A.C.

CABA

Simposio; Frontiers in Bioscience 3; 2018

IBioBA CONICET-MPSP y MPG

Tau proteins bind strongly to microtubules and are abundant in neurons. In these cells, they play a key role in the modulation of tubulin dynamics and axonal transport, among others. Tau deregulation leads to neurodegenerative diseases known as taupathies which are characterized by the formation of intracellular tau deposits. These aggregates are composed mainly of hyperphosphorylated tau. Hsp90 is a major cellular chaperone that forms large complexes with a variety of co-chaperones like the inmunophilin FKBP51. This complex has been described as a potential enhancer of abnormal tau stability by inhibiting its proteasomal degradation. Our group has described that FKBP51 SUMOylation, which is enhanced by the SUMO E3 ligase PIAS4, is essential in order to interact with Hsp90. Taking this into account, we hypothesize that PIAS4 could regulate tau stability. Our results show that PIAS4 promotes tau and phospho tau accumulation. This is dependent on PIAS4 E3-ligase activity. Interestingly, the increase in tau stability mediated by PIAS4 does not depend on tau SUMOylation, because this enzyme is unable to induce SUMO conjugation to tau. Accordingly, PIAS4 also enhances tau K340R (SUMOylation mutant) stability. PIAS4 reduces tau ? microtubules binding as shown by the loss of network distribution. This could be the consequence of an increase in phosphorylated tau driven by the ligase. Finally, our assays suggests that PIAS4 enhances the interactions between tau proteins, a process that has been linked to tau pathological deregulation.