The review focuses on modifications that alter proteins after their synthesis: phosphorylation, acetylation, methylation, glycosylation, ubiquitination, SUMOylation, neddylation, citrullination and palmitoylation. These changes can determine a protein’s activity, stability, location, interactions with other molecules and participation in signaling pathways. Their importance is particularly consequential in the intestine, where the epithelium forms a physical and immunological interface with a dense microbial environment. The authors emphasize that numerous enzymes that install or remove modifications have been identified in clinical UC samples and associated with disease onset or severity, although the strength and specificity of the evidence differ considerably among modification classes. Most findings still derive from cultured cells, animal colitis models, biopsy comparisons or small clinical cohorts rather than interventional studies in patients.

Phosphorylation provides some of the clearest examples of this dual regulatory role. In dextran sulfate sodium, or DSS, mouse models of colitis, TGF-β-activated kinase 1, or TAK1, is activated through autophosphorylation and promotes downstream NF-κB signaling; pharmacological inhibition of TAK1 attenuated disease in experimental animals. The residue involved is not unambiguous, however, because TAK1 phosphorylation at threonine 187 was associated with inflammatory signaling in one study, whereas phosphorylation at serine 412 was reported to be protective in another. Focal adhesion kinase also illustrates how phosphorylation controls epithelial integrity. Its activation promotes tight-junction assembly and recovery of transepithelial electrical resistance in Caco-2 cell monolayers, while inhibition increased permeability and disrupted junctions. Evidence linking changes in this pathway directly to patient samples remains unavailable, making the precise clinical relevance less certain than the experimental observations suggest.

Acetylation and deacetylation connect gene regulation with both inflammation and cellular stress. The expression of lysine acetyltransferase 2B, or KAT2B, was reduced in inflamed colonic epithelial cells from patients with UC, and experimental suppression of KAT2B diminished production of the anti-inflammatory cytokine IL-10. Investigation of KAT2B’s histone targets identified H4K5 acetylation, rather than the previously emphasized H3K9 and H3K14 sites, as a modification that tracked closely with KAT2B expression. Knockdown in vitro also reduced H4K5 acetylation at the IL-10 promoter, but the authors say the evidence is insufficient to designate H4K5 as the primary dysregulated site. In another line of evidence, SIRT1 was found to be downregulated in the colonic epithelium of patients. Reduced SIRT1 was linked to hyperacetylation of heat shock factor 1, suppression of molecular chaperones and endoplasmic reticulum stress, although the full pathway by which SIRT1 influences these outcomes remains unresolved. Evidence connecting acetylation directly to intestinal epithelial barrier dysfunction remains comparatively limited.

Histone methylation has been associated mainly with the balance between inflammatory and regulatory T-cell populations. The methyltransferase G9A produces H3K9 dimethylation and suppresses the differentiation of Th17 cells and regulatory T cells; small-molecule inhibition attenuated colitis in experimental models. Because the balance between IL-17-producing Th17 cells and Foxp3-positive regulatory T cells is important for intestinal homeostasis, G9A is positioned as a potential contributor to adaptive immune dysregulation. EZH2 presents a more complicated picture: through H3K27 trimethylation it can restrain NF-κB activation and pro-inflammatory cytokine expression, although some of its effects appear independent of that mark. Glycosylation supplies another route between molecular modification and disease. FUT8-dependent core fucosylation was elevated in inflamed intestinal mucosa in both mouse models and patients, while FUT8 deficiency was protective in T-cell-mediated colitis. The proposed mechanism involves changes to T-cell receptor glycoproteins that impair their antigen binding and accumulation in membrane microdomains. Glycosylation also regulates E-cadherin and adherens junctions, but the precise sites controlled by GnT-III remain unresolved.

Ubiquitination evidence points to several E3 ligases and deubiquitinases that control inflammatory proteins, autophagy and cell death. RNF183 was upregulated in UC colonic tissue and correlated with the Mayo disease score, although plasma concentrations did not differ from those of healthy controls, suggesting a locally mucosal rather than systemic association. In epithelial cells, RNF183-mediated degradation of IκBα permits nuclear NF-κB signaling. Separately, RNF183 has been linked in a mouse colitis model to ubiquitination and degradation of the death receptor DR5, with downstream apoptotic effects. RNF186 mediates degradation of EPH receptor B2 and supports autophagy and pathogen clearance, whereas RNF5, which was reduced in inflamed UC tissue, promotes degradation of the damage-associated molecular pattern S100A8. Lower RNF5 expression was also associated with failure to respond to anti-TNF therapy. At the opposite side of the pathway, A20 removes K63-linked ubiquitin from RIPK3, limiting necroptosis and preserving barrier integrity; its deubiquitinating activity is itself phosphorylation-dependent, illustrating crosstalk between modification classes.

SUMOylation and neddylation extend the same regulatory architecture. UBC9, the sole mammalian E2 enzyme used in SUMO conjugation, was downregulated in DSS colitis and in patient samples, and its reduction correlated with disease severity. Experimental loss of UBC9 was accompanied by reduced Akt1 activity, while Akt1 deletion worsened colitis, supporting a UBC9–Akt1 pathway in which SUMOylation helps stabilize Akt1. The specific SUMOylation sites through which UBC9 regulates Akt1 remain unknown. The SUMO E3 ligase PIAS1 was likewise reduced in patients and mouse models. PIAS1-mediated SUMOylation of PPARγ suppressed RelA phosphorylation and NF-κB transcriptional activity, and a nanomaterial designed to increase SUMO1-modified proteins in the colon reduced colitis in mice. The deSUMOylase SENP7, by contrast, was elevated in endoscopic UC samples and in DSS models, accompanied by reduced global SUMO2/3 conjugation. Epithelial SENP7 knockdown produced anti-inflammatory effects, although its substrates and downstream mechanisms remain unidentified. NEDD8 attachment to Cullin 1 was disrupted by small-molecule interventions that reduced neddylation enzymes, inhibited NF-κB signaling and eased intestinal inflammation, but the study was designed primarily around treatment efficacy rather than a detailed analysis of neddylation; no study reported a correlation between neddylation and clinical manifestations in patients with UC.

Citrullination and palmitoylation reveal additional links between injury responses and inflammatory transcription. Citrullination is produced by calcium-dependent peptidylarginine deiminases, including PAD4, and is generally treated as irreversible because no reversing enzymes have been identified in human tissue. PAD4 staining was prominent in inflammatory cells and the lamina propria of UC biopsies. Beyond its established contribution to neutrophil extracellular traps, PAD4 may support immunothrombosis by modifying histones and other peptides, changing chromatin structure and protease behavior, inhibiting antithrombin and promoting thrombin-mediated activation of transglutaminase XIIIa. The review interprets this mechanism as potentially protective because immunothrombi form emergency barriers at injured epithelial sites and may limit severe bleeding. Palmitoylation instead emerged as a dynamic control on STAT3. ZDHHC7 attaches palmitoyl to cysteine 108, enabling STAT3 membrane localization and phosphorylation by JAK2, after which APT2 removes the lipid before nuclear entry. Higher ZDHHC7 and LYPLA2 expression in patient peripheral blood mononuclear cells correlated with IL-17A and other STAT3 target genes, linking the modification cycle to inflammatory signaling. The review notes that simultaneous elevation of enzymes with opposing functions leaves unresolved whether both processes are active and coordinated in UC.

Across these mechanisms, NF-κB emerges as a central convergence point, although PTMs can either activate or restrain it. TAK1 phosphorylation and RNF183-dependent IκBα degradation promote signaling, while EZH2-mediated H3K27 trimethylation, PIAS1-dependent PPARγ SUMOylation and neddylation of Cullin 1 inhibit it. Crosstalk is also visible within individual proteins. A20 must be phosphorylated before its deubiquitinating function is recruited to suppress RIPK3, while the STAT3 cycle depends on the ordered addition and removal of palmitoyl groups. The review notes that evidence for other interactions, including phosphorylation–SUMOylation, glycosylation–phosphorylation and ubiquitination–SUMOylation crosstalk, is not yet directly available in UC. Microbial metabolites provide an additional layer: butyrate can increase histone H3 acetylation and suppress NF-κB activity, and pharmacologically increased propionate and butyrate enhanced Sp1 phosphorylation and HIF-1α acetylation through GPR43/GPR109A/ERK1/2 signaling while inhibiting HDAC1. Direct evidence connecting acetate to PTMs in UC, and experimental evidence for propionate- or butyrate-mediated modifications beyond the reported pathway, remains limited.

The review presents post-translational modification enzymes as promising research targets, not established treatments for UC. Most are widely expressed and act on multiple substrates, creating obstacles to selective inhibition and raising concerns about toxicity in normal tissues. Crosstalk further complicates drug design because a pathway may depend on several coordinated modifications. Experimental support nevertheless comes from TAK-981, also known as subasumstat, a SUMO-activating enzyme inhibitor that has entered cancer trials and reduced inflammation in DSS- and TNBS-induced colitis models. Its activity has not established clinical efficacy in people with UC. The review identifies several additional gaps, including limited clinical data for methylation regulators, uncertain enzymes and residues controlling epithelial glycosylation, and undetermined mechanisms by which SIRT1 regulates heat shock factor 1. The authors argue that resolving these uncertainties will require tissue- and substrate-specific enzyme studies, systematic analysis of modification crosstalk and multi-omics approaches capable of connecting molecular changes to patient-specific disease biology.

Subject of Research: Post-translational regulation of immune signaling and epithelial barrier dysfunction in ulcerative colitis

Article Title: The regulatory role of post-translational modifications in the pathogenesis of ulcerative colitis

Article References: Ji, Y., & Wei, B. (2026). The regulatory role of post-translational modifications in the pathogenesis of ulcerative colitis. Molecular Biology Reports, 53(1), Article 1474. https://doi.org/10.1007/s11033-026-12623-y

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12623-y

Keywords: ulcerative colitis, post-translational modifications, NF-κB signaling, immune dysregulation, intestinal epithelial barrier, ubiquitination, SUMOylation, palmitoylation, glycosylation, microbial metabolites, regulatory, role