HMGB1: a protein that plays diverse roles depending on its subcellular location

NCBI ID: G3146

HMGB1

HMGB1: a protein that plays diverse roles depending on its subcellular location

In the cytosol, HMGB1 interacts with Beclin-1 to induce autophagy and inhibit apoptosis. In the nucleus, it regulates the expression of heat shock protein beta-1 (HSPB1), which is involved in intracellular trafficking during autophagy and the attenuation of the apoptotic response. Extracellularly, HMGB1 interacts with surface receptors such as TLR2/4, TREM1, and RAGE, leading to inflammatory responses and the upregulation of cytokines . Specifically, when HMGB1 binds TLR4, it activates macrophage/monocyte cytokine release through the NF-kappaB pathway. Interaction with RAGE modulates endothelial and tumor cell function, involving pathways mediated by Cdc42 and Rac. Moreover, HMGB1 contributes to cellular radioresistance by promoting the acetylation of histones H3 and activating DNA damage response. In summary, HMGB1 has complex roles in apoptosis, autophagy, inflammation, and DNA damage response, depending on its cellular location and interacting partners .
Based on the provided context information, HMGB1 plays a significant role in the response to Salmonella infection and selenite treatment under different conditions.

Salmonella Infection:
- Salmonella internalization triggers the ER-stress response and activates the IRE1 branch, leading to the JNK MAPK pathway activation.
- Activation of the JNK pathway results in downregulation of the transcription factor E2F1 in both infected cells and bystander cells .
- Downregulation of E2F1 leads to a decrease in the expression of numerous miRNAs .
- The decreased expression of miRNAs enhances Salmonella intracellular replication and promotes bacterial binding, internalization, and replication in bystander cells .
- HMGB1 is secreted into the extracellular milieu upon Salmonella infection, along with other proteins related to the ER-stress response.
- Secreted HMGB1 binds to the RAGE receptor on the surface of bystander cells, triggering an IRE1-mediated ER-stress response.
- Activation of the ER-stress response in bystander cells further activates the JNK pathway, leading to downregulation of E2F1 .

Selenite Treatment:
- Selenite metabolism under hypoxic conditions produces H2Se, which gradually accumulates and induces reductive stress.
- H2Se causes the reduction of HMGB1 protein, which is secreted and promotes cell autophagy by inhibiting the Akt/mTOR axis.
- Autophagy plays a dual role, with mild autophagy inhibiting apoptosis and excessive autophagy leading to autophagy-associated cell death.
- Under hypoxic conditions, H2Se can also react rapidly with O2, forming reactive oxygen species (ROS) and leading to caspase-dependent apoptosis via oxidative stress.
- ROS can oxidize the HMGB1 protein, which is secreted and promotes cell apoptosis.

Overall, HMGB1 plays a role in the activation of the ER-stress response, regulation of transcription factor E2F1, modulation of miRNA expression, and promotion of Salmonella infection or cell autophagy/apoptosis depending on the context .

Protein Name: High Mobility Group Box 1

Functions: Multifunctional redox sensitive protein with various roles in different cellular compartments. In the nucleus is one of the major chromatin-associated non-histone proteins and acts as a DNA chaperone involved in replication, transcription, chromatin remodeling, V(D)J recombination, DNA repair and genome stability (PubMed:33147444). Proposed to be an universal biosensor for nucleic acids. Promotes host inflammatory response to sterile and infectious signals and is involved in the coordination and integration of innate and adaptive immune responses. In the cytoplasm functions as sensor and/or chaperone for immunogenic nucleic acids implicating the activation of TLR9-mediated immune responses, and mediates autophagy. Acts as danger associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury (PubMed:27362237). Released to the extracellular environment can bind DNA, nucleosomes, IL-1 beta, CXCL12, AGER isoform 2/sRAGE, lipopolysaccharide (LPS) and lipoteichoic acid (LTA), and activates cells through engagement of multiple surface receptors (PubMed:34743181). In the extracellular compartment fully reduced HMGB1 (released by necrosis) acts as a chemokine, disulfide HMGB1 (actively secreted) as a cytokine, and sulfonyl HMGB1 (released from apoptotic cells) promotes immunological tolerance (PubMed:23519706, PubMed:23446148, PubMed:23994764, PubMed:25048472). Has proangiogdenic activity (By similarity). May be involved in platelet activation (By similarity). Binds to phosphatidylserine and phosphatidylethanolamide (By similarity). Bound to RAGE mediates signaling for neuronal outgrowth (By similarity). May play a role in accumulation of expanded polyglutamine (polyQ) proteins such as huntingtin (HTT) or TBP (PubMed:23303669, PubMed:25549101)

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