Figure 5. The HMGB1-mediated autophagy pathway.

(A) The dual roles of autophagy in cancer. The main process of autophagy includes formation and maturation of the phagophore, autophagosome, and autolysosome, which lead to the degradation and recycling of the sequestered contents. During tumor development and in cancer therapy, autophagy promotes both tumor suppression and tumor survival. (B) Multiple roles of HMGB1 in autophagy. Nuclear HMGB1 modulates the expression of heat shock protein β-1 (HSPB1). Loss of either HMGB1 or HSPB1 results in a phenotypically similar deficiency in mitophagy and autophagy. This pathway requires phosphorylation of HSPB1 (both Ser15 and Ser86) to modulate actin polymerization and reorganization. Cytoplasmic HMGB1 is a novel Beclin 1-binding protein active in autophagy. HMGB1 C23 and C45 is required for HMGB1 binding to Beclin 1. p53 and unc-51-like kinase 1 (ULK1) have opposing roles in regulation of the HMGB1- Beclin 1 complex formation in cancer cells. The ULK1 kinase is an essential component of the core autophagy machinery. Extracellular HMGB1 induces autophagy by receptor for advanced glycation end products (RAGE), and this role is dependent on HMGB1’s redox state.