OTULIN Interactome Reveals Immune Response and Autophagy Associated with Tauopathy in a Mouse Model

Tauopathies are neurodegenerative diseases that are pathologically characterized by accumulation of misfolded microtubule-associated protein tau aggregates in the brain. Deubiquitination, particularly by OTULIN, a unique deubiquitinase targeting methionine-1 (M1) linkages from linear ubiquitin chain assembly complex (LUBAC)), is reportedly associated with the accumulation of neurotoxic proteins in several neurodegenerative diseases, likely including tauopathies. To investigate the potential roles of OTULIN in tauopathies, we analyzed the OTULIN interactome in hippocampal tissues from PS19 transgenic (Tg) mice and their non-transgenic (nTg) littermate controls using affinity purification-mass spectrometry (AP-MS). We identified 705 and 800 proteins enriched in Tg and nTg samples, respectively, with a protein false discovery rate (FDR) of <1%. Of these, 189 and 205 proteins were classified as probable OTULIN interactors in Tg and nTg groups, respectively, based on Significance Analysis of INTeractome (SAINT) score of ≥0.80 and FDR of ≤ 5%. A total of 84 proteins were identified as OTULIN interactors in the PS19 Tg group, while 100 proteins were associated with OTULIN in the nTg controls. Functional enrichment analyses revealed that OTULIN-interacting proteins in the nTg group were enriched in pathways related to spliceosome, complement and coagulation cascades, and ribosome, whereas those in the Tg group were associated with immune response and autophagy. These findings suggest that OTULIN-interacting proteins may play a critical role in the pathogenesis of tauopathy in this mouse model.