Viruses are invaders that get inside the cells of many kinds of organisms, from single-celled microbes to plants and mammals. Virus infection is a prevalent cause of human sickness or death worldwide and a major source of hospital admissions in children, adults and the elderly, significantly impacting healthcare systems and human health (1, 2). The coordination of antiviral immune responses in the innate immune system, which is the first line of defense against viral infection, is required (3, 4). The innate immune system is a universal and ancient host defense against infection that recognizes nonspecific pathogens (5, 6). Most innate immune cells have molecular receptors that are genetically conserved. The immune system uses these innate immune receptors, also known as pattern recognition receptors (PRRs), including retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), toll-like receptors (TLRs), nucleotide oligomerization domain-like receptors (NLRs), c-type lectin receptors (CLRs), and others (7). PRRs are used to identify structurally conserved molecules known as pathogen-associated molecular patterns (PAMPs), which are shared by a wide range of microbial species. Even though PAMPs from viruses, bacteria, fungi, and parasites have a wide variety of chemical structures, the immune response brought on by innate immunity cells is quick (8). Infection with a virus or an immunostimulant mimic, such as poly (I:C), can trigger the synthesis of interferon-β (IFN-β), a vital element of innate antiviral immunity (9).

HDACs are acetylation erasers from lysine residues that play critical roles in many biological processes, including immunity, cell cycle progression, apoptosis, and their repressive effects on gene transcription (10–12). HDACs have been classified into four classes in humans. Up to this point, four distinct classes of HDACs have been identified: class I (HDAC1, HDAC2, HDAC3, and HDAC8), class II (quite far subdivided into IIa comprising of HDAC4, HDAC5, HDAC7, HDAC9 and IIb consisting of HDAC6, HDAC10), class III (Sirtuins 1-7) and class IV (HDAC11) (13, 14). Except for class III, eleven of the 18 HDACs rely on Zn²⁺ for deacetylation (15). Class II HDACs are known to often move between the nucleus and cytoplasm, whereas those of class IIb HDACs are mostly localized in the cytoplasm (16). Immune cells react to invaders’ single- or double-stranded DNA or RNA in a general manner during this viral invasion. HDACs modulate this response by enhancing or weakening the results to alter genetic signatures. The JAK/STAT pathway, which is the most crucial signaling pathway against viral infection, is activated by type-I interferon (IFN-I) (17). It is noteworthy that HDAC3 interacts with forkhead box K1 to control signaling STAT1/2 transcription, which supports macrophages’ antiviral innate immunity (18). To control the expression of the interferon-stimulated gene (ISG), the released IFN cytokines first bind to IFN-I receptors and activate the JAK/STAT signaling cascade (19). HDAC4, a class II member, has anti-influenza A virus (IAV) characteristics and is a component of the host’s innate antiviral response (20). Besides, HDAC1 is crucial for the replication of the IAV, suggesting that it could be a target for innate immunity-based antiviral protection (21). HDAC6 is essential for antiviral innate immune responses (22–24). HDAC6 was first discovered due to its similarity to the Saccharomyces cerevisiae histone deacetylase HDA1 (25, 26). Moreover, HDAC6 is a multisubstrate enzyme that controls several cellular processes, including those that lead to cancer, neurological illnesses and inflammatory disorders. However, it is still unclear how HDAC6 is related to the antiviral signaling network and whether it is essential for antiviral immunity in animals under physiological circumstances. In particular, data show that IFN-β gene activation necessitates HDAC activity and that HDAC6 also serves as a coactivator of interferon regulatory factor 3 (IRF3)-dependent transcription (19). The failure of IFN-β production in cells is linked to the inhibition of antiviral responses (19). As a result of these factors, HDAC6 has emerged as a topic of intense interest among researchers and has become a desirable therapeutic target.

To conclude, we highlight new studies that show HDAC6’s multi-functionality in protein structure, viral infection, innate immune response, upstream signaling, and the application of HDAC6 inhibitors in associated diseases.

The HDAC6 isoenzyme has two deacetylase domains. This enzyme is a cytoplasmic class II histone deacetylase involved in a variety of cellular functions such as immunological synapse formation, misfolded protein degradation, migration, and cell-cell contact (27, 28). With 1,215 amino acids, HDAC6 protein is the largest HDAC protein found in people. It is unique and different because it is made up of five domains. The N-terminal (1-87 aa) is made up of a nuclear-localized signal (NLS, 14-59 aa) and a nuclear export signal (NES, 67-76 aa), which together control HDAC6’s shift from the nucleus to the cytoplasm. Also, research shows that the N-terminal of HDAC6 is needed for binding and effective acetylation of tubulin (29); it has two highly conserved catalytic domains, the first of which is called catalytic domain 1 (CD1, 88-447 aa) and has been shown to have deacetylase activity (30) and ubiquitin E3 ligase activity (31); the second CD2 (482-800 aa) exhibits broader substrate specificity as a deacetylated domain with catalytic activity (32); a cytoplasmic retention signal, Ser-Glu-containing tetrapeptide (SE14, 884-1022 aa), SE14 has the ability to control how HDAC6 interacts with other proteins (33). Another NES (1049-1058 aa) and a zinc-finger ubiquitin-specific protease (ZnF-UBP domain, also known as BUZ, 1131-1192 aa) recruit ubiquitin protein to stimulate aggresome formation ( Figure 1 ) (34–36). The HDAC6 gene has 21923 base pairs and is on chromosome X p11.22-23. It is found in large amounts in the testis, spermatogenic cells, germ cell tissues, liver, heart, muscle, spleen, and kidney, among other normal human tissues and organs. ( Figure 2 ) (Data from https://www.ncbi.nlm.nih.gov/gene/10013) (25, 37, 38).

Also, HDAC family members, especially the cytoplasmic protein HDAC6, are very important in controlling the acetylation of non-histone (34). A proteomic analysis found at least 3,600 acetylation sites in 1,750 nuclear and non-nuclear proteins. This shows that acetylation and deacetylation play an important role in processes in both the nucleus and the cytoplasm (39). Many substrates and proteins that work with them are found in the cytoplasm, which makes sense since that is where HDAC6 was found to be concentrated. HDAC6 has been shown to interact with a number of proteins that are not histones. These include α-tubulin (40, 41), heat shock protein 90 (42), cortactin (43), peroxiredoxins (44), β-catenin (45), Ku-70 (46), Tat (47), survivin (48), extracellular signal-regulated kinase-1 (ERK-1) (49, 50), heat shock factor-1 (51), myosin heavy chain 9 (52), heat shock cognate protein 70 (52), dnaJ homolog subfamily A member 1 (52), Miro-1 (53), tripartite motif-containing protein 21 (TRIM21) (22). Table 1 is a summary of the many HDAC6 substrates, what they do, and what viral infections they are linked to. A proteomics study found that 107 proteins in the livers of HDAC6 knockout mice could be HDAC6 deacetylating substrates (52).

HDAC6’s tubulin deacetylase activity was initially reported by Hubbert et al. in both in vivo and in vitro settings (40). In the end, it was found that the activity of HDAC6 recombinant mutants is controlled by mutations in certain catalytic domains. Their analysis showed that in vitro deacetylase activity was only encountered in the CD2 domain (35). In contrast to other HDACs, HDAC6 has a Cys/His-rich C-terminal region that interacts with polyubiquitin in a novel way while preserving the deacetylase activity of the protein (37). It has been reported that HDAC6 inhibitors regulate viral infection, tumorigenesis and disease development. Specific HDAC6 inhibitors are known so far including Tubacin, Tubastatin A, ACY-1215, ACY-24, Nexturastat A and others (34). HDAC6 inhibitors are gradually being used as a novel strategy for antiviral and antitumor drug development.

The host antiviral response depends on understanding HDAC6’s upstream signaling molecules. Transactive response DNA-binding protein 43 kDa (TDP-43), a nuclear RNA binding protein, is important in RNA processing (70, 71). TDP-43 particularly binds HDAC6 RNA, according to current research (65). TDP-43 stabilises the antiviral enzyme HDAC6 and increases its mRNA and protein levels, the study found (65). The upregulation of MT acetylation and the downregulation of the antiviral HDAC6 enzyme in response to low TDP-43 levels make target cells more vulnerable to human immunodeficiency virus (HIV) infection (65). High TDP-43 levels, on the other hand, change the cellular level of the HDAC6 antiviral factor, preventing HIV-1 envelope complex (Env) fusion and infection regardless of viral Env tropism and strain (65). The acetylation of α-tubulin lysine-40 amino acids is considered a sign of microtubules (MTs) stability (72), and as early as 2022, researchers found that HDAC6 can deacetylate α-tubulin (73). Rabies is caused by the Rabies virus, which has a high fatality rate and offers a significant health risk to humans. It was shown that expressing the rabies virus M protein alone significantly increased HDAC6 expression, leading to a significant decrease in its substrate, acetylated-tubulin, and ultimately MTs depolymerization (74) ( Figure 3A ). MTs depolymerization increases viral RNA production substantially (74). Inhibiting HDCA6 deacetylase activity drastically reduced rabies virus RNA synthesis, indicating that HDAC6 plays an essential role in viral infection. The protein kinase C (PKC) family is a type of serine/threonine kinase that is activated by phospholipids and calcium (75). PKCα is a member of the PKC family that is implicated in cancers, viral infection, and other signaling pathways (75, 76). Although IRF3 activation controls interferon synthesis, a recent study has demonstrated that IRF3 also works in conjunction with the protein β-catenin (69). A previous study has shown that HDAC6 activates β-catenin by deacetylation (69). However, following viral infection, how β-catenin was activated to affect downstream signaling pathways is still elusive. Zhu et al. (24) demonstrated a signaling pathway involving sendai virus (SeV) infection activated PKCα, which increases the phosphorylation of HDAC6, which then deacetylates β-catenin and promotes its translocation to the nucleus, promotes the phosphorylation of IRF3 and the production of IFN-β, which eventually lead to the inhibition of SeV replication ( Figure 3B ).

HDAC6 regulates both DNA and RNA viral replication, with recent research concentrating on influenza viruses among RNA viruses. HDAC6 mainly confronts virus invasion by controlling host cytoskeleton MTs to dynamically control virus transport, fusion, or uncoating. HDAC6 can also control viral infection by modifying the human immune system and autophagy. HDAC6’s upstream signaling pathway and its downstream target in anti-viral signaling, regrettably, remain largely unknown. Recent research on HDAC6 activity emphasizes its importance in the innate immune response to viral infection. Studies on HDAC6’s function in the infection of viruses have mostly focused on three aspects: (a) controlling viral transport, fusion, and viral component release by modulating plasma membrane dynamics and the cytoskeleton (55, 56, 62, 63, 74, 77); (b) influencing host cells’ antiviral immune response (19, 23, 69); (c) tuning the breakdown of viral or host proteins in host cells through autophagy (64, 68, 78).

More attention has been paid to HDAC6’s many roles in pathology and physiology because it could be used to treat a wide range of diseases. Recent studies and reports have shown that selective HDAC6 inhibition is a good way to fight neurodegenerative diseases like Alzheimer, Huntington, and Parkinson (140). The cells of the innate immune system are the most important line of defense against pathogens and cancer cells. HDAC6 is closely linked to a number of diseases that are linked to cancerous tumors (141). As well as cancers like lung cancer, breast cancer, and ovarian cancer (28). In the case of hepatocellular carcinoma (HCC), pro-inflammatory cytokines increase the amount of HDAC6 in the body. This can cause more cells to grow by stopping p53 from doing its job as a transcription factor and causing it to be broken down (142). Hepatitis B virus (HBV), as a stronger inducer of HCC, chronic infection of HBV increased risk of HCC (143, 144). According to research, the protein expression levels of HDAC6 in HBV patients’ serum and liver decreased significantly after antiviral treatment (145). It has been reported that HBV internalization is sparked by the host-entry cofactor epidermal growth factor receptor (146). A deficiency of HDAC6 promotes epidermal growth factor receptor endocytic trafficking and degradation (147). In addition, the study found that HDAC6 can promote human papillomavirus (HPV) positive cervical cancer by upregulating Wnt5a (148). In the small-cell lung cancer xenograft model, HDAC6 was found to be a possible treatment target when used with JQ1 (149). More research needs to be done to find out if HDAC6 overexpression mice cause tumors or if they are more or less likely to get tumors. The innate immune response is different and ends with the production of cytokines (150). A macrophage releases ILs, cytokines that give instructions to other immune cells when it encounters a virus, bacteria, or other pathogens (151, 152). The innate immune response is a quick, nonspecific reaction that is controlled by a number of molecules. HDACs are important for controlling the size and strength of the response, which makes it possible to make just the right amount of inflammatory cytokines and ILs (153). Early-onset familial Parkinson’s disease is caused by changes in the protein Parkin, which is a ubiquitin ligase (154). Parkin increases mitophagy by accelerating mitochondrial ubiquitination, which attracts ubiquitin-binding autophagic components, HDAC6 and p62, resulting in mitochondrial clearance (154). Tubulin deacetylation is caused by the enzymatic activity of HDAC6 (40), and blocking tubulin deacetylation is effective in avoiding neurodegeneration in animal models of Alzheimer’s and Huntington’s disease (155, 156).

Through the transcriptional activation of their respective genes by a transcription factor NF-κB, which is a crucial component of the immune response, these cytokines are frequently produced by a variety of innate immune cells, HDAC6 has a role in HIV-1 Tat-induced pro-inflammatory gene expression by regulating the mitogen-activated protein kinase NF-κB/AP-1 pathways and it is a biological target for HIV-1 Tat-mediated neuroinflammation (60, 61). Interestingly, HDAC6 is also involved in the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic that is currently underway (coronavirus disease 2019; COVID-19) (157). HDAC6 inhibition has the potential to be used to minimize the morbidity associated with severe COVID-19 via modulating the innate and adaptive immune systems (54). HDAC6 inhibition, which blocks IFN-I synthesis and its downstream effects in airway epithelial cells and immune cells, may be able to mitigate the negative effects generated in severely ill COVID-19 patients by late or extended activation of the IFN-I pathway (54). These results support the use of HDAC inhibitors as part of an epigenetic therapeutic strategy in the treatment of severe COVID-19 (54).

HDAC6 may be a risk factor for tuberculosis (TB) and a novel host-directed anti-TB therapeutic target (158). HDAC6 also affects allergic skin inflammation. By directly modulating sirtuin 1 expression, HDAC6-negative MiR-9 prevented atopic dermatitis (159). HDAC6 and CXCL13 influence cellular connections and miR-9 and SIRT1 expression (159). HDAC6 regulates inflammation. HDAC6 reduces NACHT, LRR, and PYD domains-containing protein (NLRP3) inflammasome activity by interacting with ubiquitinated NLRP3 (160). HDAC6 knockout mice develop normally, but their immune systems are weakened (38). HDAC6 promotes monocyte/macrophage infiltration during inflammation and suppresses T cell IL-17 production, providing new insights into its role in the immune system (161, 162). A recent study demonstrated that administering an HDAC6 degrader to LPS-induced mice reduced the activation of the NLRP3 inflammasome, confirming for the first time that HDAC6 proteolysis targeting chimera may be a potential treatment for NLRP3-related illnesses (163).

Tubacin, as a selective inhibitor of HDAC6, plays a positive role in anti-viral and anti-tumor diseases (164–166). It is worth noting that “tubacin”, which prevents α-tubulin deacetylation in mammalian cells, was discovered for the first time using an omnifarious, chemical genetic screen of 7,392 small molecules (167). In the early years, as an HDAC6 selective inhibitor, tubacin induces apoptosis in epstein-barr virus (EBV)-burkitt lymphoma cells and kills EBV lymphoblastoid cells by producing reactive oxygen species (165). A few years ago, researchers found that tubacin reduces Japanese encephalitis virus replication by reducing viral RNA synthesis (164). The role of inhibiting viral replication was also demonstrated by HDAC inhibitors including suberoylanilide hydroxamic acid (SAHA) (168), which improves the susceptibility of uninfected CD4+ T cells to HIV by boosting the kinetics and efficiency of postentry viral processes (169). On the other hand, HDAC6 knockout mice can live and grow normally, tubulin hyperacetylation does not interfere with normal mammalian development, indicating that HDAC6 inhibitors could have less negative effects (38), as opposed to the inhibition of specific class I HDACs and other HDACs. These results encourage more research into the efficacy of HDAC6 inhibitors in a variety of diseases, including hematological malignancies (170, 171), neurodegenerative diseases (140) and cancers (28). Moreover, specific inhibition of HDAC6 normalizes B cell activation and germinal centre development in a model of systemic lupus erythematosus (172). These tests will provide the basic science foundation for moving forward with clinical trials of an inhibitor that selectively targets HDAC6. There is great potential for HDAC6 as a target molecule in clinical drug research, as more than a dozen HDAC6s are already in use for the treatment of various disorders.

This review summarizes the function of HDAC6 in viral infection, host antiviral immunity and immune-related disorders. HDAC6 is a cytoplasmic class II histone deacetylase involved in various cellular functions, including immunological synapse formation, misfolded protein degradation, migration, and cell-cell contact. HDAC6 has two highly conserved catalytic domains: catalytic domain 1 (CD1) and CD2, which exhibit broader substrate specificity as a deacetylated domain with catalytic activity. Another NES (1049-1058 aa) and a ZnF-UBP domain recruit ubiquitin protein to stimulate aggresome formation. The HDAC6 gene has 21923 base pairs and is on chromosome X p11.22-23. It is found in large amounts in the testis, spermatogenic cells, germ cell tissues, liver, heart, muscle, spleen, and kidney, among other normal human tissues and organs. HDAC6 functions as a host antiviral factor to prevent the invasion and infection of invaders, while the virus will utilize some HDAC6 properties to escape the host’s defensive response and aid in the virus’s intracellular cycle completion. HDAC6 can reduce IAV release by deacetylating MTs, inhibit viral transcription by inhibiting the IAV RNA polymerase PA subunit, and assist viral uncoating via the aggregation formation mechanism of HDAC6’s ZnF domain. Blocking HDAC6 binding of ZnF to ubiquitin can decrease aggregation formation, reducing IAV uncoating. HDAC6 is involved in the process of a range of viral infections and can be exploited as a potential therapeutic target for many disorders. Therefore, the review’s findings show that HDAC6 is an attractive and new potential therapeutic target for the development of immune-enhancing medicines in the areas of antiviral immunity, innate immune response, and certain diseases.

MQ and XW conceived and drafted the manuscript. MQ, YS, AW and PC discussed the concepts of the manuscript. MQ drew the figures. MQ, XY, XW, HZ and YS approved the version to be submitted. All authors contributed to the article and approved the submitted version.