New insights into the non-enzymatic function of HDAC6

Yuanzai Zhu; Mengkai Feng; Bo Wang; Yichao Zheng; Dandan Jiang; Lijuan Zhao; M A A Mamun; Huiqin Kang; Haiqian Nie; Xiya Zhang; Ningjie Guo; Shangshang Qin; Ning Wang; Hongmin Liu; Ya Gao

doi:10.1016/j.biopha.2023.114438

New insights into the non-enzymatic function of HDAC6

Biomed Pharmacother. 2023 May:161:114438. doi: 10.1016/j.biopha.2023.114438. Epub 2023 Mar 9.

Authors

Yuanzai Zhu¹, Mengkai Feng¹, Bo Wang², Yichao Zheng¹, Dandan Jiang³, Lijuan Zhao¹, M A A Mamun¹, Huiqin Kang¹, Haiqian Nie¹, Xiya Zhang¹, Ningjie Guo¹, Shangshang Qin¹, Ning Wang⁴, Hongmin Liu⁵, Ya Gao⁶

Affiliations

¹ State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
² State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450001, China.
³ Department of Pharmacy, People's Hospital of Henan Province, Zhengzhou University, Henan 450001, China.
⁴ The School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
⁵ State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: liuhm@zzu.edu.cn.
⁶ State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, Henan Province, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Institute of Drug Discovery and Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: ya_gao@zzu.edu.cn.

PMID: 37002569
DOI: 10.1016/j.biopha.2023.114438

Abstract

Histone deacetylase 6 (HDAC6) is a class IIb histone deacetylase that contains two catalytic domains and a zinc-finger ubiquitin binding domain (ZnF-UBP) domain. The deacetylation function of HDAC6 has been extensively studied with common substrates such as α-tubulin, cortactin, and Hsp90. Apart from its deacetylase activity, HDAC6 ZnF-UBP binds to unanchored ubiquitin of specific sequences and serves as a carrier for transporting aggregated proteins. As a result, aggresomes are formed and protein degradation is facilitated by the autophagy-lysosome pathway. This HDAC6-dependent microtubule transport can be used by cells to assemble and activate inflammasomes, which play a critical role in immune regulation. Even viruses can benefit from the carrier of HDAC6 to assist in uncoating their surfaces during their infection cycle. However, HDAC6 is also capable of blocking virus invasion and replication in a non-enzymatic manner. Given these non-enzymatic functions, HDAC6 is closely associated with various diseases, including neurodegeneration, inflammasome-associated diseases, cancer, and viral infections. Small molecule inhibitors targeting the ubiquitin binding pocket of HDAC6 have been investigated. In this review, we focus on mechanisms in non-enzymatic functions of HDAC6 and discuss the rationality and prospects of therapeutic strategies by intervening the activation of HDAC6 ZnF-UBP in concrete diseases.

Keywords: Aggresome; Autophagy; HDAC6 ZnF-UBP; Inflammasomes; Non-enzymatic function; Therapeutic strategy.

Publication types

Review

MeSH terms

Carrier Proteins / metabolism
Histone Deacetylase 6 / metabolism
Histone Deacetylases* / metabolism
Protein Binding
Ubiquitin* / metabolism

Substances

Histone Deacetylase 6
Histone Deacetylases
Ubiquitin
Carrier Proteins