Biology subjects

Rajaiya, J.

Publications and source records attributed to Rajaiya, J..

3 recordsLinked to original sources

bioRxiv2025

OCT4 Negatively Regulates the Transcriptional Programming of the Early Region 3 Immune Evasion Genes of Human Adenovirus

Genomes of viruses are constrained by the virions nanoscale, and viral nucleotide sequences without function are a luxury. Yet the double-stranded DNA genome of human adenovirus (HAdV) contains large regions without known purpose. Using TRANSFAC and ChIP-Seq analysis, we identified binding of OCT4 (octomer-binding transcription factor 4) to a noncoding region of HAdV-D37 DNA. Manipulation of OCT4 expression impacted viral E3 gene transcription and gp19k protein expression, altering subsequent MHC Class I expression. These effects were specific to OCT4 binding to the adenovirus 5' inverted terminal repeat (ITR) within nucleotides 101-159. Using targeted mutations to OCT4, we found one of two OCT4 binding motifs in the ITR to be crucial for repression of E3 gene expression. In OCT4-siRNA treated cells, E3 RID- gene expression was also upregulated to inhibit pro-apoptotic signals, suggesting that OCT4 binding also indirectly represses viral replication. Consistent with a role for transcription factors in epigenetic modification during infections, OCT4 knockdown also reduced histone H3 acetylation and DNA methylation. In stem cells, OCT4 sustains pluripotency, whereas in somatic cells, OCT4 plays a dispensable role in self-renewal and maintenance. Herein, we show that OCT4 binding also confers a previously unidentified function to non-coding adenovirus DNA. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/650321v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1a94a11org.highwire.dtl.DTLVardef@13dc8e5org.highwire.dtl.DTLVardef@1505f22org.highwire.dtl.DTLVardef@195be29_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Targeting CRM1-HMGB1 Nuclear Translocation in Type 2 Diabetes-Driven Metabolic Dysfunction Associated Steatotic Liver Disease

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) prevalent in Type-2 Diabetes (T2D) and contributes to progression of Non-Alcoholic Steatohepatitis (NASH). Acetyl-High Mobility Group Box 1 (HMGB1,) a proinflammatory isoform of HMGB1, is released as a DAMP in T2D associated hepatic inflammatory condition. Chromosomal Maintenance 1 (CRM1), a nuclear transporter protein, maintains the nuclear-cytoplasm translocation of hepatic HMGB1 in T2D. We hypothesize that inhibition of CRM1/HMGB1 nuclear shuttling is a therapeutic target for MASLD in T2D. Methods: We performed immunohistochemical analysis of acetyl-HMGB1 and CRM1 in human liver biopsies from control, T2D, and T2D-NASH (n:4 per group). H&E staining to evaluate inflammation and disease stratification. In vitro, studies involved targeted inhibition of CRM1 using Leptomycin-B and HMGB1 with Glycyrrhizin in T2D Huh7 human hepatocytes. Results: T2D subjects with NASH exhibit an increase in acetyl-HMGB1 nuclear and cytoplasmic translocation compared to DM and controls. Acetyl-HMGB1 increased 2-fold in the nucleus and 4-fold in the cytoplasm; CRM1 increased 6-fold in the nucleus and 8-fold in the cytoplasm of T2D/NASH subjects compared to controls. Targeted inhibition of CRM1 and HMGB1 prevented acetyl-HMGB1 hepatocyte release with the most prominent effect in T2D-NASH conditions. Conclusions: Hepatic CRM1/HMGB1 inhibition could be a potential therapeutic target for T2D-driven MASLD.

pathology↗

bioRxiv2025

Virus and Cell Specific HMGB1 Secretion and Subepithelial Infiltrate Formation in Adenovirus Keratitis

A highly contagious infection caused by human adenovirus species D (HAdV-D), epidemic keratoconjunctivitis (EKC) results in corneal subepithelial infiltration (SEI) by leukocytes, the hallmark of the infection. To date, the pathogenesis of corneal SEI formation in EKC is unresolved. HMGB1 (high-mobility group box 1 protein) is an alarmin expressed in response to infection and a marker of sepsis. Earlier studies using a different adenovirus species, HAdV-C, showed retention of HMGB1 in the infected cell nucleus by adenovirus protein VII, enabling immune evasion. Here, using HAdV-D we show cell-specific HMGB1 secretion by infected cells, and provide an HAdV-D specific mechanism for SEI formation in EKC. HMGB1 was secreted only upon infection of human corneal epithelial cells, not from other cell types, and only upon infection by HAdV-D types associated with EKC. Acetylated HMGB1 translocation from the nucleus to the cytoplasm, then to the extracellular milieu, was tightly controlled by CRM1 and LAMP1, respectively. Primary stromal cells when stimulated by rHMGB1 expressed proinflammatory chemokines. In a novel 3D culture system in tune with the architecture of the cornea, HMGB1 released by infected corneal epithelial cells induced leukocytic infiltrates either directly and/or indirectly via stimulated stromal cells, which together explains SEI formation in EKC.

microbiology↗