Zinc-finger ubiquitin-binding domain of histone deacetylase 6 modulates Tau structure and function

Histone deacetylase 6 (HDAC6), a predominantly cytoplasmic deacetylase, has emerged as a critical regulator of protein homeostasis, and plays an important role in neurodegenerative disorders characterized by Tau pathology. We investigated the role of zinc-finger ubiquitin-binding domain (ZnF UBP) of HDAC6 in modulating tau structure and function. HDAC6 is well known for its deacetylase activity and involvement in aggresome formation but the functional contribution of its ZnF UBP domain in tau biology remains not well explored. Using a combination of biochemical, biophysical, and molecular approaches, we demonstrate that the ZnF UBP domain of HDAC6 directly interacts with tau, influencing its conformational dynamics and aggregation propensity. Our findings reveal that this interaction is independent of HDAC6's catalytic deacetylase activity, highlighting a non-canonical mechanism through which HDAC6 regulates tau. Structural analyses indicate that binding of ZnF UBP induces conformational rearrangements in tau, potentially altering its microtubule-binding capacity and aggregation behavior. Furthermore, we show that the HDAC6-tau interaction modulates tau aggregation, suggesting a protective or regulatory role in preventing aberrant tau aggregation. Functional assays support the notion that ZnF UBP-mediated modulation of tau contributes to maintaining cytoskeletal integrity and cellular proteostasis. These observations suggests that HDAC6 functions not only as a deacetylase but also performs regulatory functions through ZnF UBP domain that can influence the function and properties of intrinsically disordered proteins (IDPs) like tau. Overall, this chapter provides mechanistic insights into the non-enzymatic functions of HDAC6, specifically through its ZnF UBP domain, in regulating tau structure and function. Understanding this interaction expands the current perspective on HDAC6 biology and underscores its potential as a therapeutic target in tauopathies, including Alzheimer's disease and targeting domain-specific interactions of HDAC6 may offer a novel therapeutic strategy to modulate tau pathology.