Jade1S SUMOylates tau and targets oligomers for degradation

Abstract

The accumulation of insoluble tau aggregates is a pathological hallmark of tauopathies, including Alzheimer's disease. While molecular chaperones and clearance pathways regulate tau homeostasis, the mechanisms governing tau oligomerization and degradation remain incompletely defined. Recent genome-wide association studies (GWAS) have linked the JADE1 locus to tauopathy, and the PHD zinc finger protein Jade1S has been identified in complexes with tau in post-mortem brain tissue, prompting investigation into their biochemical relationship. Here, we characterize the reciprocal interactions between Jade1S and 0N4R tau stability and turnover. Covalent labeling mass spectrometry and co-immunoprecipitation mappings reveal that Jade1S binds wild-type 0N4R tau through redundant sites within its N-terminal and plant homeodomain (PHD) zinc finger domains. In vitro assays demonstrate that Jade1S functions as a SUMO E3 ligase, utilizing its PHD domains to mediate tau SUMOylation. Cell-based cycloheximide chase assays reveal a reciprocal stabilization dynamic: tau co-expression extends the overall physiological half-life of Jade1S from less than an hour to ~17 hours, arresting its turnover specifically within sarkosyl-insoluble fractions. Conversely, Jade1S selectively accelerates the degradation of sarkosyl-insoluble tau without altering the turnover of the soluble monomeric pool over chased time. Mechanistically, Jade1S redirects the clearance of SUMO2/3-modified tau oligomers away from basal autophagic-lysosomal pathways and toward proteasome-dependent degradation. Furthermore, Jade1S exhibits intrinsic molecular chaperone activity, inhibiting arachidonic acid-induced tau oligomerization in vitro. Together, these data characterize Jade1S as a dual-function SUMO ligase and chaperone that regulates tau stability, prevents oligomer assembly, and promotes the targeted proteasomal clearance of aggregated tau.