Multifunctional acyltransferase HBO1: a key regulatory factor for cellular functions

Abstract

HBO1, also known as KAT7 or MYST2, is a crucial histone acetyltransferase with diverse cellular functions. It typically forms complexes with protein subunits or cofactors such as MEAF6, ING4, or ING5, and JADE1/2/3 or BRPF1/2/3, where the BRPF or JADE proteins serve as the scaffold targeting histone H3 or H4, respectively. The histone acetylation mediated by HBO1 plays significant roles in DNA replication and gene expression regulation. Additionally, HBO1 catalyzes the modification of proteins through acylation with propionyl, butyryl, crotonyl, benzoyl, and acetoacetyl groups. HBO1 undergoes ubiquitination and degradation by two types of ubiquitin complexes and can also act as an E3 ubiquitin ligase for the estrogen receptor α (ERα). Moreover, HBO1 participates in the expansion of medullary thymic epithelial cells (mTECs) and regulates the expression of peripheral tissue genes (PTGs) mediated by autoimmune regulator (AIRE), thus inducing immune tolerance. Furthermore, HBO1 influences the renewal of hematopoietic stem cells and the development of neural stem cells significantly. Importantly, the overexpression of HBO1 in various cancers suggests its carcinogenic role and potential as a therapeutic target. This review summarizes recent advancements in understanding HBO1's involvement in acylation modification, DNA replication, ubiquitination, immunity, and stem cell renewal.

Keywords: Acetylation; DNA replication; HBO1; Immune regulation; Ubiquitylation.

Fig. 1

HBO1 complexes and gene expression. HBO1 forms complexes with other proteins to acetylate histones and promote the expression of multiple genes. The HBO1 complex with BRPF as the scaffold mainly targets histone H3 acetylation, while the HBO1 complex with JADE as the scaffold mainly targets histone H4 acetylation. The histone acetylation will promote the expression of many genes including SIX1, CNTTB1, HOXA9, HOXA10, p21/CDKN1A, and GADD45A

Fig. 2

HBO1-mediated histone acetylation in DNA replication. HBO1-mediated histone acetylation promotes G1 phase DNA replication licensing and S phase DNA replication activation. In the G1 phase, the HBO1–JADE complex promotes the acetylation of H4K5/8/12 to relax the chromatin conformation, and facilitates the loading of the MCM complex to the replication starting point, promoting the assembly of the pre-replication complex. In S phase, the HBO1–BRPF3 complex specifically directs H3K14ac, thereby promoting CDC45 loading to activate S-phase DNA replication. Additionally, the regulatory protein Geminin prevents the second round of DNA replication by inhibiting the basic replication factor CDT1, possibly by inhibiting HBO1

Fig. 3

HBO1 involvement in DNA repair after UV irradiation. HBO1 plays a crucial role in the DNA repair process after UV irradiation, primarily associated with global genome nucleotide excision repair (GG-NER). Following UV-induced DNA damage, DDB2 recognizes the cyclobutyl pyrimidine dimer (CPD) site, and phosphorylated HBO1 binds to DDB2, mediating histone acetylation. HBO1 also maintains the chromatin remodeling agent ACF1–SNF2H at the damage site, inducing chromatin remodeling. Additionally, the methyltransferase MLL1 interacts with HBO1 and localizes at the UV damage site to methylate histone H3K4. BAZ1A, a subunit of the SWI/SNF chromatin remodeling factor, targets trimethylated histone H3K4 (H3K4me3). These mechanisms collectively disrupt the interaction between DNA and histones, facilitating the loading of NER factors including XPC for DNA repair

Fig. 4

Ubiquitination and degradation of HBO1. HBO1 can undergo ubiquitination by the SCF (SKP1/Cullin-1/Fbxw15) and CRL4 (DDB1-CUL4A-RBX1) complexes. Protein kinase MEK1 phosphorylates HBO1, promoting its degradation via the Fbxw15-mediated ubiquitin proteasome pathway. In mouse lung epithelial cells (MLE-12), LPS induces HBO1 degradation through this pathway. Conversely, LPS stimulation in THP-1 monocytes and human primary macrophages inhibits HBO1 ubiquitination by increasing the level of deubiquitinase USP25 protein, resulting in varying degrees of HBO1 protein elevation. Furthermore, DNA damage caused by UV irradiation leads to the degradation of HBO1 by the DDB2-mediated CRL4 (DDB1–CUL4A–RBX1) complex

Fig. 5

HBO1 promotes immune-related gene expression via histone acetylation. BRPF2 and HBO1 form complexes that bind to the enhancer and promoter of the CD8 gene, respectively. Together, they acetylate histone H3 at lysine 14 (H3K14ac) at the CD8 locus, leading to full activation of the CD8 gene. The BRPF2–HBO1 complex also interacts directly with key regulatory factors, such as the RUNX family transcription factors and Ikaros, to activate CD8 gene expression. SCML4, a transcription factor crucial for CD8+ resident memory T cells (Trm) and tumor-infiltrating lymphocytes (TIL), recruits the HBO1–BRPF2–ING4 complex to mediate H3K14ac, thereby enhancing chromatin accessibility during T cell activation and increasing the expression of T cell effector molecules, such as interferon-gamma (IFNG) and granzyme B (GZMB)