E3 Ligases and Deubiquitinases in Controlling High-Mobility Group Box (HMGB) Protein Functions

High-Mobility Group Box (HMGB) proteins belong to the family of high-mobility proteins characterized by two DNA-binding domains and an unstructured, negatively charged C-terminal domain that modulates DNA–protein and protein–protein interactions. These proteins participate in multiple cellular processes, including DNA replication, transcription, recombination, and repair. The functional activity of HMGB proteins is associated with various physiological and pathological conditions, including malignant tumors and cardiovascular diseases, highlighting the need for strict regulation of their levels and activity to maintain cellular homeostasis. Such regulation can occur at multiple levels, including proteolytic degradation. In recent years, a number of E3 ubiquitin ligases that promote the degradation of HMGB proteins, as well as deubiquitinases (DUBs) that stabilize them by removing ubiquitin tags, have been identified. This review summarizes these enzymes and their proposed roles in controlling the functions of the HMGB family proteins, both through direct interaction with these proteins and via mediator proteins.