HMGB1 Signaling

High Mobility Group-B1 (HMGB1) is a DNA binding protein involved in assembly of nucleoprotein complexes, maintenance of nucleosome structure and regulation of gene transcription. It has a role in neurite outgrowth, smooth muscle cell chemotaxis, inflammatory responses and tumor metastasis.HMGB1 is secreted by macrophages, monocytes, and pituicytes after stimulation with endotoxins. In all cells, HMGB1 shuttles between nucleus and cytoplasm; nuclear import is active, and the protein migrates back to the cytoplasm via passive diffusion and exportin 1 (XPO1)-mediated active export. When HMGB1 is under acetylated, the rate of nuclear import exceeds that of rediffusion plus export, and the protein appears predominantly or solely nuclear. Activation of inflammatory cells through binding of IL-1, TNF-α, IFN-γ, LPS or HMGB1 itself to their own receptors (IL-1R, TNFR1, TLR4, IFN-γR and RAGE respectively), activates the NF-κB and MAPK pathways. Phosphorylated MAPKs and NF-κB migrate to the nucleus and lead to the activation of histone acetylases (HATs) or inhibition of deacetylases. This in turn promotes acetylation of HMGB1. Exported acetyl-HMGB1 cannot return to the nucleus.Myeloid cells are equipped with secretory lysosomes, that can be secreted upon appropriate stimulation and that can accumulate HMGB1, presumably through specific transporters embedded in the lysosomal membrane. Upon binding of lysophosphatidylcholine (LPC), to its receptor, the secretory lysosomes carrying HMGB1 fuse with the plasma membrane and secrete HMGB1 to the extracellular space. Necrotic cells release HMGB1 by simple diffusion, and thereby trigger inflammation; in contrast, apoptotic cells avidly retain HMGB1 bound to chromatin remnants even after their eventual lysis.HMGB1 can activate cell surface receptors on various cell types through ERK1/2 and JNK and p38; PI3K and Akt; the transcription factors NF-κB and Sp1 as well as Rac1 and CDC42.HMGB1 signals through the receptor for advanced glycation end-products (RAGE), a multiligand receptor of the immunoglobulin superfamily, expressed on monocytes and macrophages. Cell activation by HMGB1 results in the release of a proinflammatory cytokines and chemokines: TNF-α, IL-1α, IL-1β, IL-1Ra, IL-6, IL-8 and MCP1, upregulation of adhesion molecules: ICAM1 and VCAM1, RAGE, and HMGB1 itself. TNF-α acts locally to amplify responses initiated by HMGB1. HMGB1-mediated proinflammatory responses have multiple effects at various sites. HMGB1 signals to the cell motility system by activating CDC42, Rac1 and Rho. Convergence of HMGB1 binding to RAGE on CDC42-Rac1-MKK6-p38 MAPK to upregulate myogenin and MHC expression accelerate myotube formation.At the lamellopodia, HMGB1 interacts with the extracellular matrix and membrane receptors, affecting cell motility and metastasis. In the developing nervous system, membrane-associated HMGB1 localizes to growth cones and promotes neurite outgrowth and extension by binding to RAGE. In neural tissue and malignant cells, RAGE activation by HMGB1 leads to MAPK activation and is associated with enhanced tumor growth, metastases, and release of MMPs. Extracellular HMGB1 and RAGE induce both migration and proliferation of vessel-associated stem cells, and thus may play a role in muscle tissue regeneration. HMGB1 plays a pivotal role in the pathogenesis of chronic arthritis and it may mediate strong, direct bactericidal effects. Targeting the HMGB1 or its receptor represents an important potential application in cancer therapeutics.