HMGB1 and autophagy

scientific reports hmgb1

High mobility group box 1 (HMGB1) is a non-histone chromosome binding protein, and its function involves gene transcription, gene recombination, DNA damage repair and other biological processes. Overexpression of HMGB1 is one of the characteristics of certain tumors that correlates with the ability of tumors to proliferate, angiogenesis, and programmed death, and can attenuate the surveillance of growth signals, inflammatory responses, tumor tissue infiltration and metastasis effect. The study found that HMGB1 plays a central role in the development of tumors and the healing of multiple injuries. The role of HMGB1 in tumors, especially in the development of tumors, and the progress of targeted therapy targeting HMGB1 and its receptors have received extensive attention.

HMGB1 is present in almost all multicellular organisms. Initially, it was thought that it was rich in acidic amino acids and alkaline amino acids in a class of chromatin related proteins[1]. HMGB1 is a highly conserved nuclear protein that binds to DNA as a chromosome binding protein and promotes transcription of related genes after protein synthesis [2,3]. In the extracellular HMGB1 involved in inflammatory response, cell differentiation, cell migration and tumor metastasis [2 ~ 5]. The interaction between HMGB1 and advanced glycation end product (RAGE) is closely related to the development of tumorigenesis [6,7].

1 HMGB1 structure, expression and function

HMGB1 has two DNA binding regions, called A box and B box, each binding region length of 75 amino acid residues, in addition, there is a negatively charged C-terminal tail, with continuous glutamic acid And the aspartic acid amino acid sequence [1, 8]. This molecule is highly conserved, and its post-translational modifications include a variety of forms, including glycosylation, acetylation, methylation, phosphorylation [3,9], in which only acetylated HMGB1 and homologous DNA polymerase alpha Form a specific complex and activate the enzyme [10], while acetylation and phosphorylation can cause HMGB1 transport from the nucleus to the cytoplasm. In most tumors, the expression of HMGB1 was regulated by transcription factors p53 [11], c-Myc [12]and Kruppel-like factor 4 (KLF-4) [13]. HMGB1 is expressed consistently in both the normal and the nuclei of cancer cells. Natural acetylated HMGB1 from tumor cells itself can block DNA replication, whereas recombinant HMGB1 does not have this function, but protein kinase C can phosphorylate recombinant HMGB1 in vitro to regain this function [ 14]. HMGB1 can also activate the activity of a variety of transcription factors, which is extremely important in the development of cancer. These transcription factors include p53 [15 ~ 18], p73 [11,19], Rb protein [20,21], Rel / NF-?B family [22] and nuclear hormone receptors including estrogen receptors. The cells that produce stress or the death of the cells release HMGB1, the release of extracellular HMGB1 in the tumor has a contradictory dual role. On the one hand, it can promote the formation of tumor neovascularization and can trigger protective antitumor T cell responses [23]; on the other hand, it can promote the tumor antigen presenting function of mature DC by TLR-4 [23]. In vitro and in vivo experiments show that neutralization or knockout of HMGB1 or TLR-4 can make the body anti-tumor immune response disappeared [24].

2 HMGB1 in apoptotic and autophagy

HMGB1 was thought to be a marker of cell necrosis, but later it was found that both autophagia and apoptotic cells could release HMGB1 [25-29]. The role of HMGB1 in the process is different depending on the type of cell and the stress received. HMGB1 can block the apoptosis of yeast cells through Bak-Bak-family Bak, and HMGB1 can also inhibit the apoptosis of yeast cells by overexpression of fibronectin [30]. HMGB1 also helps cells escape apoptosis caused by UV, CD95, TRAIL, Casp-8 and Bax [31]. HMGB1 expression in human cancer tissue was significantly increased, which is related to the up-regulation of anti-apoptotic protein c-IAP2 [32]. After tumor radiotherapy and chemotherapy, HMGB1 in the tumor cells and other cytokines were released together to form a local disorder of the microenvironment [33]. The effect of HMGB1 on tumor immunity in such a microenvironment is bi-directional: on the one hand it promotes angiogenesis, and it stimulates the response of protective antitumor T cells [23]. HMGB1 can directly or indirectly regulate autophagy: on the one hand, HMGB1 can interact directly with the autophagy protein Beclin1, leaving it directly from Bcl-2 to regulate autophagy [34]; on the other hand, in tumor cells and immune cells HMGB1 can promote MEK-ERK activity [27,35 ~ 37], while MEK-ERK signaling pathway can regulate autophagy by directly modulating Beclin1 [38], suggesting that HMGB1 can regulate autophagy indirectly. HMGB1 has important biological significance for the regulation of autophagy. RAGE / HMGB1 maintains autophagy and inhibits apoptosis to maintain the survival of pancreatic cancer cells and colon cancer cells [34,39,40]. HMGB1 activates autophagy directly through the PI3KC3- MEK-ERK signaling pathway to regulate the formation of autophagosomes [41].



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