HIPK2 phosphorylates HDAC3 for NF-κB acetylation to ameliorate colitis-associated colorectal carcinoma and sepsis

Abstract

Although inflammation is critical for the clearance of pathogens, uncontrolled inflammation also contributes to the development of multiple diseases such as cancer and sepsis. Since NF-κB–mediated transactivation in the nucleus is pivotal downstream of various stimuli to induce inflammation, searching the nuclear-localized targets specifically regulating NF-κB activation will provide important therapeutic application. Here, we have identified that homeodomain-interacting protein kinase 2 (HIPK2), a nuclear serine/threonine kinase, increases its expression in inflammatory macrophages. Importantly, HIPK2 deficiency or overexpression could enhance or inhibit inflammatory responses in LPS-stimulated macrophages, respectively. HIPK2-deficient mice were more susceptible to LPS-induced endotoxemia and CLP-induced sepsis. Adoptive transfer of Hipk2+/− bone marrow cells (BMs) also aggravated AOM/DSS-induced colorectal cancer. Mechanistically, HIPK2 bound and phosphorylated histone deacetylase 3 (HDAC3) at serine 374 to inhibit its enzymatic activity, thus reducing the deacetylation of p65 at lysine 218 to suppress NF-κB activation. Notably, the HDAC3 inhibitors protected wild-type or Hipk2−/− BMs-reconstituted mice from LPS-induced endotoxemia. Our findings suggest that the HIPK2-HDAC3-p65 module in macrophages restrains excessive inflammation, which may represent a new layer of therapeutic mechanism for colitis-associated colorectal cancer and sepsis.

HDAC3-Regulated PGE2 Production by Microglia Induces Phobic Anxiety Susceptibility After Stroke and Pointedly Exploiting a Signal-Targeted Gamma Visual Stimulation New Therapy

“…Furthermore, we found that Cox1, as the target gene downstream of NF-kB signalling, depends on HDAC3 regulation. As proven by a previous report, HDAC3 contains deacetylase (DA)dependent deacetylation of p65, in line with previous literature indicating that p65 is a direct substrate of HDAC3 and that deacetylation triggers the nuclear export of p65 (43,44). Therefore, HDAC3 regulating PGE 2 synthesis may be attributed to deacetylating p65, as our data proved.…”

Separation of transcriptional repressor and activator functions in HDAC3

“…This explains older results showing that the C-terminus is necessary for catalytic activity (Yang et al, 2002). Since the C-terminus can be phosphorylated by several kinases (Sengupta and Seto, 2004; Seo et al, 2019; Tsai and Seto, 2002; Zhang et al, 2021; Zhang et al, 2005), it suggests that the HDAC3-DAD domain interaction is regulated by signaling. Furthermore, a recent study showed that NADPH inhibits HDAC3-DAD domain complex formation by competing with IP4 for binding to HDAC3 (Li et al, 2021b).…”

The phosphorylation to acetylation/methylation cascade in transcriptional regulation: how kinases regulate transcriptional activities of DNA/histone-modifying enzymes

“…For HDAC3 phosphorylation, it is interesting that phosphorylated Ser424 increases HDAC3 activity, but several protein kinases are reported to be involved in, including CK2, TANK-binding kinase (TBK1), leucine-rich repeat kinase 2 (LRRK2), c-Jun N-terminal kinase (JNK), and PTEN-induced putative kinase 1 (PINK1) [ 139 – 143 ]. The other site, Ser374, is phosphorylated by homeodomain-interacting protein kinase 2 (HIPK2), which inhibits the enzymatic activity of HDAC3 [ 144 ]. Similarly, the enzymatic activity of HDAC8 is repressed by PKA-mediated phosphorylation at Ser39 [ 145 , 146 ].…”