PIAS4 SUMO E3 ligase modulates tau and phospho-tau levels

R GOBBINI; S SENIN; ML BUDZIÑSKI; E ARZT; C SOKN; M ERDOCIA; AC LIBERMAN

Congreso; XXXIII Reunion Cientifica Anual en Investigación Clínica; 2018

Over the past few years, SUMO conjugation has been increasingly related with neurological diseases associated with abnormal protein accumulations. In particular, some of the PIAS SUMO-E3 ligases are directly linked to these processes. These E3 ligases can regulate protein-protein interactions, intracellular trafficking as well as aggregation and degradation of key neuronal substrates, therefore the dysregulation of their activity is linked to neurodegeneration. Among the different neurodegenerative diseases, tauopathies are characterized by the formation of intracellular tau deposits. These aggregates are composed mainly of hyperphosphorylated tau, but also some other modified tau species such as ubiquitinated and SUMOylated tau. SUMOylation of tau proteins may contribute to changes in protein solubility and proteolytic processing. However, the intrinsic molecular mechanism and its physiological relevance is still under investigation. In this work we evaluated the ability of PIAS family members (PIAS1, PIAS2a, PIAS2b, PIAS3 and PIAS4) to modulate total and phospho-tau intracellular levels. We found that PIAS4 promotes tau and phospho-tau accumulation, increasing tau stability probably by inhibiting it´s degradation by the ubiquitin-proteasome system. PIAS4 effect over tau protein is dependent on PIAS4 E3 ligase activity.. In this work we show that PIAS4 has several effects on tau protein. It promotes tau and phospho (pS262) tau accumulation probably by inhibiting tau proteasomal degradation. Interestingly, the PIAS4 mutant lacking the ligase activity doesn´t reproduce PIAS4 WT effect on tau and phospho tau levels suggesting that SUMOylation is involved in this process. PIAS4 also reduces tau ? microtubules binding as shown by the loos of network distribution in the confocal images of cells cotransfected with tau-BifC plasmids. This could be the consequence of the higher proportion of pS262-tau molecules driven by the ligase overexpression. pS262-tau molecules are known to bind less tightly to microtubules compare to the unphosphorylated form. Finally, the BifC assay suggests that PIAS4 enhances the interactions between tau proteins, a process that has been linked to tau pathological deregulation