Abstract
High-mobility group box 1 protein (HMGB1) shows endogenous damage-associated molecular patterns (DAMPs) and is also an early warning protein that activates the body’s innate immune system. Here, the full-length coding sequence of HMGB1 was cloned from the spleen of Cherry Valley duck and analyzed. We find that duck HMGB1(duHMGB1) is mostly located in the nucleus of duck embryo fibroblast (DEF) cells under normal conditions but released into the cytoplasm after lipopolysaccharide (LPS) stimulation. Knocking-down or overexpressing duHMGB1 had no effect on the baseline apoptosis rate of DEF cells. However, overexpression increased weakly apoptosis after LPS activation. In addition, overexpression strongly activated the IFN-I/IRF7 signaling pathway in DEF cells and significantly increased the transcriptional level of numerous pattern recognition receptors (PRRs), pro-inflammatory cytokines (IL-6, TNF-α), IFNs and antiviral molecules (OAS, PKR, Mx) starting from 48 h post-transfection. Overexpression of duHMGB1 strongly impacted duck virus replication, either by inhibiting it from the first stage of infection for novel duck reovirus (NDRV) and at late stage for duck Tembusu virus (DTMUV) or duck plague virus (DPV), or promoting replication at early stage for DTMUV and DPV infection. Importantly, data from duHMGB1 overexpression and knockdown experiments, time-dependent DEF cells transcriptional immune responses suggest that duHMGB1 and RIG-I receptor might cooperate to promote the expression of antiviral proteins after NDRV infection, as a potential mechanism of duHMGB1-mediated antiviral activity.
Highlights
High-mobility group box 1 protein (HMGB1) belongs to a family of nonhistone chromosomal proteins, which are widely conserved in the nucleus of eukaryotic cells
DuHMGB1 was branched with birds and showed higher evolutionary relationship than with mammals and fish (Figure 1B)
The alignment of multiple sequences generated by ClustalW2 showed that the duck HMGB1 (duHMGB1) displayed high sequence identity with HMGB1 of chicken (99%), human (89%), or mouse (89%), suggesting that HMGB1 is highly conserved across species (Figure 1C)
Summary
High-mobility group box 1 protein (HMGB1) belongs to a family of nonhistone chromosomal proteins, which are widely conserved in the nucleus of eukaryotic cells. HMGB1 was discovered in the 1960s and was named for its high migration ability in polyacrylamide gel. HMGB1 has two nuclear localization sequences and no endoplasmic reticulum localization sequence; HMGB1 is normally located in the nucleus. Proper signal stimulation leads to high acetylation of HMGB1 resulting in cytosolic relocation [3]. HMGB1 has different redox states due to the different extracellular redox environment. HMGB1 in the all-thiol state acts primarily on the RAGE receptor resulting in the production and release of pro-inflammatory cytokines and chemokines [4]. When presented in the oxidative environment, cysteines 23 and 46 in the HMGB1 A box form a sulfide bond effectively producing the disulfide
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