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Post-Translational Modification of HMGB1 Disulfide Bonds in Stimulating and Inhibiting Inflammation.
Andersson, Ulf; Tracey, Kevin J; Yang, Huan.
  • Andersson U; Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, 17176 Stockholm, Sweden.
  • Tracey KJ; Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
  • Yang H; Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
Cells ; 10(12)2021 11 26.
Article in English | MEDLINE | ID: covidwho-1551567
ABSTRACT
High mobility group box 1 protein (HMGB1), a highly conserved nuclear DNA-binding protein, is a "damage-associated molecular pattern" molecule (DAMP) implicated in both stimulating and inhibiting innate immunity. As reviewed here, HMGB1 is an oxidation-reduction sensitive DAMP bearing three cysteines, and the post-translational modification of these residues establishes its proinflammatory and anti-inflammatory activities by binding to different extracellular cell surface receptors. The redox-sensitive signaling mechanisms of HMGB1 also occupy an important niche in innate immunity because HMGB1 may carry other DAMPs and pathogen-associated molecular pattern molecules (PAMPs). HMGB1 with DAMP/PAMP cofactors bind to the receptor for advanced glycation end products (RAGE) which internalizes the HMGB1 complexes by endocytosis for incorporation in lysosomal compartments. Intra-lysosomal HMGB1 disrupts lysosomal membranes thereby releasing the HMGB1-transported molecules to stimulate cytosolic sensors that mediate inflammation. This HMGB1-DAMP/PAMP cofactor pathway slowed the development of HMGB1-binding antagonists for diagnostic or therapeutic use. However, recent discoveries that HMGB1 released from neurons mediates inflammation via the TLR4 receptor system, and that cancer cells express fully oxidized HMGB1 as an immunosuppressive mechanism, offer new paths to targeting HMGB1 for inflammation, pain, and cancer.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protein Processing, Post-Translational / HMGB1 Protein / Disulfides / Inflammation Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: Cells10123323

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protein Processing, Post-Translational / HMGB1 Protein / Disulfides / Inflammation Limits: Animals / Humans Language: English Year: 2021 Document Type: Article Affiliation country: Cells10123323