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Review
. 2023 Aug 11:14:1216548.
doi: 10.3389/fimmu.2023.1216548. eCollection 2023.

Histone deacetylase 6's function in viral infection, innate immunity, and disease: latest advances

Min Qu  1 , Huijun Zhang  1 , Pengyuan Cheng  1 , Ashenafi Kiros Wubshet  1   2 , Xiangping Yin  1 , Xiangwei Wang  1 , Yuefeng Sun  1
Affiliations
Review

Histone deacetylase 6's function in viral infection, innate immunity, and disease: latest advances

Min Qu et al. Front Immunol. .

Abstract

In the family of histone-deacetylases, histone deacetylase 6 (HDAC6) stands out. The cytoplasmic class IIb histone deacetylase (HDAC) family is essential for many cellular functions. It plays a crucial and debatable regulatory role in innate antiviral immunity. This review summarises the current state of our understanding of HDAC6's structure and function in light of the three mechanisms by which it controls DNA and RNA virus infection: cytoskeleton regulation, host innate immune response, and autophagy degradation of host or viral proteins. In addition, we summed up how HDAC6 inhibitors are used to treat a wide range of diseases, and how its upstream signaling plays a role in the antiviral mechanism. Together, the findings of this review highlight HDAC6's importance as a new therapeutic target in antiviral immunity, innate immune response, and some diseases, all of which offer promising new avenues for the development of drugs targeting the immune response.

Keywords: HDAC6; autophagy; diseases; innate immunity; viral infection.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Human HDAC6’s functional domains and schematic depiction. HDAC6 has both catalytic activity and two tandem deacetylase domains (CD1 and CD2). Two nuclear export signal (NES) prevents the protein from building up in the nucleus, and the Ser-Glu-containing tetrapeptide (SE14) region guarantees persistent anchoring of the enzyme in the cytoplasm. In the nucleus, HDAC6 is translocated by the nuclear localization signal (NLS). The C terminal contains a ZnF-UBP.
Figure 2
Figure 2
Human HDAC6 RNA expression level in normal tissues. The data from National Center for Biotechnology Information. HDAC6 is abundant in the kidney, testis, liver and brain. RPKM means reads per kilobase of exon model per million mapped reads.
Figure 3
Figure 3
Effects of HDAC6 on RNA virus infection and host antiviral immunity. (A) By upregulating HDAC6, the M protein of the rabies virus induces MTs depolymerization to facilitate viral RNA synthesis. (B) HDAC6 deacetylation of β-catenin promotes nuclear translocation and IRF3-mediated IFN-β transcription, thereby inhibiting the infection by SeV. (C) HDAC6 prevents HIV-1 replication by deacetylating Tat and decreasing its ability to transactivate. (D) By interacting with RIG-I and promoting RIG-I deacetylation and sensing of RNA viruses, HDAC6 accelerates the transmission of the RLR signaling pathway when it is overexpressed, which increases the production of IFN-β and inflammatory proteins to prevent viral infection. (E) HDAC6 prevents the production of HIV-1 by promoting the degradation of viral proteins Pr55Gag and Vif. Ac, acetyl; M, matrix protein of rabies virus; P, phosphorylation; RABV, rabies virus.
Figure 4
Figure 4
HDAC6 promotes or inhibits IAV replication and infection interestingly. (A) HDAC6 inhibits IAV release by downregulating IAV viral component transport by deacetylating MTs. (B) HDAC6 interacts with dynein, IAV can promote virus uncoating by utilizing the HDAC6-Znf-dependent aggresome formation mechanism. (C) DARPins block the binding of HDAC6-ZnF to Ub, inhibit the production of downstream SGs and impair IAV infection. (D) Through the destabilization of PA, HDAC6 functions as a negative regulator of IAV infection. HDAC6 binds to and deacetylates PA, promoting its proteasomal degradation. PA, polymerase acidic protein; MT, microtubule; Ub, ubiquitin.
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Grants and funding

This work was sponsored by the Major Science and Technology Project of Gansu Province (21ZD3NA001, 22ZD6NA001), the Key Development and Research Foundation of Gansu (Grant no. 21YF5WA153) and National Natural Science Foundation of China (Grant no. 32202779).