The relationship between HMGB1 and autophagy in the pathogenesis of diabetes and its complications

Abstract

Diabetes mellitus is a chronic metabolic disorder characterized by elevated blood glucose levels and has become the third leading threat to human health after cancer and cardiovascular disease. Recent studies have shown that autophagy is closely associated with diabetes. Under normal physiological conditions, autophagy promotes cellular homeostasis, reduces damage to healthy tissues and has bidirectional effects on regulating diabetes. However, under pathological conditions, unregulated autophagy activation leads to cell death and may contribute to the progression of diabetes. Therefore, restoring normal autophagy may be a key strategy to treat diabetes. High-mobility group box 1 protein (HMGB1) is a chromatin protein that is mainly present in the nucleus and can be actively secreted or passively released from necrotic, apoptotic, and inflammatory cells. HMGB1 can induce autophagy by activating various pathways. Studies have shown that HMGB1 plays an important role in insulin resistance and diabetes. In this review, we will introduce the biological and structural characteristics of HMGB1 and summarize the existing knowledge on the relationship between HMGB1, autophagy, diabetes, and diabetic complications. We will also summarize potential therapeutic strategies that may be useful for the prevention and treatment of diabetes and its complications.

Keywords: HMGB1; TCM; autophagy; diabetes; diabetic complication.

Figure 1

The mechanism of autophagy and its regulation. Molecular circuits and signaling pathways that regulate autophagy. Autophagy is a complex self-degradation process involving the following key steps: the control of Beclin-1/VPS34-mediated formation of phagosomes on the ER and other membranes in response to stress signaling pathways; Atg5-Atg12 conjugation and interaction with Atg16L and the multimerization of the phagosome; LC3 processing and insertion into the extended phagosome membrane; the capture of random or selective targets for degradation to complete the autophagosome while ATG4 recycles some LC3-II/ATG8; and autophagosome fusion with lysosomes and proteolytic degradation of the engulfed molecules by lysosomal proteases. Autophagy is regulated by important signaling pathways in cells, including stress signaling kinases such as JNK-1, which promotes autophagy by phosphorylating Bcl-2, thereby promoting the interaction of Beclin-1 with VPS34. Perhaps the core signaling molecule that determines the level of autophagy in cells is the kinase mTOR, which can mediate its effect on autophagy by inhibiting the ATG1/Ulk-1/-2 complex in the earliest stage of lipid bilayer phagophore formation. mTOR is key to integrating metabolic factors, growth factors, and energy signals associated with autophagy. On the one hand, mTOR inhibits autophagy when nutrients are abundant, and on the other hand, mTOR signaling stimulates growth-promoting activities, including protein translation. Autophagy is induced by hypoxia and low cytoplasmic ATP levels, which feed through REDD1 and AMP kinase to inhibit mTOR activity by reducing RhebGTPase activity. Conversely, increased growth factor signaling through the insulin receptor and its adapter IRS1 and other growth factor receptors that activate class I PI3 kinase and Akt inhibits autophagy and promotes mTOR activity by inhibiting TSC1/TSC2 and increasing RhebGTPase activity.

Figure 2

Signaling pathways are regulated by autophagy in diabetes. Diabetes affects autophagy through the following pathways: oxidative stress, endoplasmic reticulum stress, mTOR-dependent signaling pathway, and the AMPK pathway. Autophagy maintains ROS levels by removing partially depolarized mitochondria, and ROS can activate autophagy by inhibiting mTOR, increasing Beclin-1 expression, and converting LC3-I to LC3-II. ROS can act as signaling molecules that activate JNK-1, and large amounts of ROS lead to the opening of the mitochondrial permeability transition pore, which disrupts mitochondrial membrane potential and leads to the onset of PINK1/parkin-mediated autophagy. ROS can also induce autophagy through regulation at the transcriptional level (in the nucleus) and translational level (in the cytoplasm), and an increase in ROS activates the transcription factors HIF-1α, p53, FOXO3, and Nrf2 and promotes the transcription of BNIP3, NIX, TIGAR, LC3, and p62. Endoplasmic reticulum stress induces autophagy through the UPR pathway and endoplasmic reticulum Ca2+ transport. The IRE1α pathway activates the cJun-N-terminal kinase (JNK) pathway and modification of x-box binding protein 1 (XBP1) mRNA by a shift mutation. The ATF6 pathway regulates other UPR members including XBP1. The PERK pathway affects autophagy by inducing the transcription of autophagy-related genes such as ATG5, ATG7, and ATG10 through ATF4. The PERK pathway also facilitates the conversion of LC3-I to LC3-II induced by polyglutamine 72 (PolyQ72). In the early stages of endoplasmic reticulum stress, activated IRE1α phosphorylates Bcl-2, which is involved in the induction of autophagy, via the JUK pathway, leading to the separation of Bcl-2 from Beclin-1. In addition, another participant of the XBP-1-IRE1α pathway promotes Beclin-1 transcription. ATF6 is indirectly involved in autophagy by inducing XBP-1 transcription. Under ER stress, excessive Ca2+ entry into the cytoplasm induces autophagy through three different mechanisms: Stimulation of the CamKK/AMPK-dependent pathway leading to mTOR inhibition; Activation of death-associated protein kinase (DAPK) by participating in the phosphorylation of Beclin-1; and activation of the PKC pathway leading to Bcl2-Beclin-1 complex segregation.

Figure 3

Mutual regulation mechanism of autophagy and HMGB1. Intracellular HMGB1 regulates cellular autophagy by binding with Beclin1. In the cytoplasm, HMGB1 mainly binds to Beclin1 to promote the dissociation of Beclin1 and anti-apoptotic factor Bcl-2, leading to the activation of autophagy through the interaction between Beclin1 and PI3K ClassIII/Vsp34. The specific mechanism of this process is that the semi-cysteine residues at positions 23 and 45 of the A-box of HMGB1 can form disulfide bridges with Beclin1, which results in the dissociation of Beclin1 from Bcl-2. HMGB1 regulates cellular autophagy by binding with cell membrane receptor RAGE, which can be actively secreted or passively released into the extracellular space during cell death. In the extracellular space, HMGB1 regulates cellular autophagy mainly by binding with RAGE. In the nucleus, HMGB1 participates in regulating the expression of heat shock protein B1 (HSPB1). The activation of phosphorylated HSPB1 at positions 15 and 86 by HMGB1 has an important effect on the polymerization and reorganization of the cytoskeleton, which is crucial for intracellular substance transport. HMGB1 is mainly located in the cell nucleus, and the HSP90AA1-dependent transport is involved in the nuclear-cytoplasmic translocation of HMGB1. When HMGB1 translocates to the cytoplasm, its secretion requires autophagy and vesicular transport, which can be enhanced by HSP90AA1. Upon external stimulation, autophagy can promote the translocation of HMGB1 from the nucleus to the cytoplasm through a ROS-dependent pathway, thereby replacing Bcl-2 and binding with Beclin1, which activates autophagy and further maintains it.

Figure 4

Regulation of the interplay between autophagy and HMGB1 in islet injury. HMGB1 promotes early inflammation in diabetes and leads to necrosis in islet cells. Necrotic cells release HMGB1, which activates TLRs and RAGE on macrophages and dendritic cells. The activation of TLRs and RAGE leads to the translocation of NF-κB into the nucleus to promotes the expression of inflammatory genes, which contributes to the secretion of proinflammatory cytokines, including HMGB1. In addition, activated macrophages and dendritic cells actively secrete HMGB1, exacerbating islet cell necrosis. HMGB1 can competitively interact with Beclin-1 to disrupt the Beclin-1/Bcl-2 interaction, which promotes autophagy.