The extracellular HDAC6 ZnF UBP domain modulates the actin network and post-translational modifications of Tau

Cell Communication and Signaling

Abhishek Ankur Balmik¹  Subashchandrabose Chinnathambi¹  Shweta Kishor Sonawane¹ 

[1] Neurobiology Group, Division of Biochemical Sciences, CSIR-National Chemical Laboratory (CSIR-NCL), Dr. Homi Bhabha Road, 411008, Pune, India;Academy of Scientific and Innovative Research (AcSIR), 201002, Ghaziabad, India;

关键词: HDAC6;    Tau;    Phosphorylation;    Tauopathies;    Microtubule;    Actin;    Podosomes;    Podonut;    Actin;    Cytoskeleton;    Neurodegeneration;   

DOI  :  10.1186/s12964-021-00736-9

来源: Springer

【 摘 要 】

BackgroundMicrotubule-associated protein Tau undergoes aggregation in Alzheimer`s disease (AD) and a group of other related diseases collectively known as Tauopathies. In AD, Tau forms aggregates, which are deposited intracellularly as neurofibrillary tangles. Histone deacetylase-6 (HDAC6) plays an important role in aggresome formation, where it recruits polyubiquitinated aggregates to the motor protein dynein.MethodsHere, we have studied the effects of HDAC6 ZnF UBP on Tau phosphorylation, ApoE localization, GSK-3β regulation and cytoskeletal organization in neuronal cells by immunocytochemical analysis. This analysis reveals that the cell exposure to the UBP-type zinc finger domain of HDAC6 (HDAC6 ZnF UBP) can modulate Tau phosphorylation and actin cytoskeleton organization.ResultsHDAC6 ZnF UBP treatment to cells did not affect their viability and resulted in enhanced neurite extension and formation of structures similar to podosomes, lamellipodia and podonuts suggesting the role of this domain in actin re-organization. Also, HDAC6 ZnF UBP treatment caused increase in nuclear localization of ApoE and tubulin localization in microtubule organizing centre (MTOC). Therefore, our studies suggest the regulatory role of this domain in different aspects of neurodegenerative diseases. Upon HDAC6 ZnF UBP treatment, inactive phosphorylated form of GSK-3β increases without any change in total GSK-3β level.ConclusionsHDAC6 ZnF UBP was found to be involved in cytoskeletal re-organization by modulating actin dynamics and tubulin localization. Overall, our study suggests that ZnF domain of HDAC6 performs various regulatory functions apart from its classical function in aggresome formation in protein misfolding diseases.BbeLHN_zgyG8Hf4zoSkS1nVideo abstract

【 授权许可】

CC BY