High mobility group proteins (HMG proteins)

High mobility group (HMG) proteins are a superfamily of abundant, non-histone nuclear proteins that play critical roles in organizing chromatin architecture and regulating DNA-dependent processes such as transcription, replication, and repair [1.2.1, 1.3.2]. They are classified into three distinct families—HMGA, HMGB, and HMGN—each characterized by unique functional domains like the AT-hook, HMG-box, and nucleosome-binding domain, respectively [1.3.1, 1.4.1]. While primarily nuclear, certain members like HMGB1 can be actively secreted by immune cells or passively released from damaged cells, acting as potent extracellular alarmins or damage-associated molecular patterns (DAMPs) [1.1.2, 1.2.2]. In the extracellular space, HMGB1 triggers pro-inflammatory signaling by interacting with receptors such as RAGE and TLR4, contributing to the pathogenesis of sepsis, chronic inflammation, and cancer [1.1.3, 1.4.2]. Therapeutic strategies targeting HMG proteins focus on inhibiting their release, neutralizing their extracellular activity with antibodies or small molecules like glycyrrhizin, or blocking their downstream receptor interactions [1.5.1, 1.5.2]. However, the dual role of these proteins as essential nuclear factors and pathological extracellular mediators presents significant challenges for drug development, particularly regarding the maintenance of genomic stability and normal immune function [1.5.4].

Other names

HMGsHigh mobility group superfamilyNon-histone chromosomal proteinsHigh mobility group box proteinsHigh mobility group AT-hook proteinsHigh mobility group nucleosome-binding proteins

Drugs targeting HMG proteins, particularly HMGB1, primarily act by inhibiting their active secretion from immune cells, neutralizing their extracellular activity through direct binding, or competitively antagonizing their interaction with pro-inflammatory receptors such as RAGE and TLR4 [1.1.1, 1.1.5, 1.5.1].