Molecular insights into the multifaceted functions and therapeutic targeting of high mobility group box 1 in metabolic diseases

Abstract

HMGB1 is a ubiquitously expressed protein localized in nucleus, cytoplasm, as well as secreted into extracellular space. Nuclear HMGB1 binds to DNAs and RNAs, regulating genomic stability and transcription. Cytoplasmic HMGB1 regulates autophagy through binding to core autophagy regulators. Secreted extracellular HMGB1 functions as a ligand to various receptors (RAGE and TLRs, etc.), regulating multiple signalling pathways, such as MAPK, PI3K and NF-κB signallings. Trafficking and localization of HMGB1 across cellular compartments could be regulated by its posttranslational modifications, which fine-tune its functions in metabolic diseases, inflammation and cancers. The current review examines the up-to-date findings pertaining to the biological functions of HMGB1, with focus on its posttranslational modifications and roles in downstream signalling pathways involved in metabolic diseases. This review also discusses the feasibility of targeting HMGB1 as a potential pharmacological intervention for metabolic diseases.

Keywords: advanced glycation end products; autophagy; genomic stability; inflammation; toll-like receptors.

FIGURE 1

Primary sequence of HMGB1 and its posttranslational modification sites. Human HMGB1 consists of 215 amino acids, which comprises A‐box (red solid box), B‐box (blue solid box) and acidic tail (red background). HMGB1 is phosphorylation at Ser39, Ser53 and Ser181. HMGB1 is N‐glycosylated at Asn37, Asn134 and Asn135. Redox sensitivity and disulfide linkages that may occur at amino acid positions of Cys23, Cys45 and Cys106 in HMGB‐1 require additional evaluation, as indicated by ‘?’. HMGB1 is hyperacetylated at multiple sites of lysine in two nuclear localization sequences (NLS). Green colour indicates acetylation sites, red colour indicates phosphorylation sites, blue colour indicates glycosylated sites, and purple colour indicates disulfide bound sites. Yellow background indicates oxidized and reduced sites. Question marks indicate site modifications needed re‐evaluation. Dashed boxes indicate the NLS domains

FIGURE 2

Schematic diagram of HMGB1’s function in the cytoplasm, nucleus and extracellular spaces. (A) In the nucleus, HMGB1 binds (such as promotors of YAP, HSBP1) and bends DNA, which maintains genome stability and regulates gene transcriptions. (B) In the cytoplasm, HMGB1 binds to protein partners and facilitate various cellular function, such as the binding of Beclin1 in the process of autophagy. (C) In the extracellular space, HMGB1 binds to several receptors, such as TLR2, TLR4 and RAGE, and regulates downstream signalling pathways, including MAPK, PI3K, NF‐κB and JAK/STAT, which are essential in signalling network of diseases