Editorial

2 pages, 192 KiB

Open AccessEditorial

by Aída Barreiro-Alonso, Ángel Vizoso-Vázquez, Mónica Lamas-Maceiras and María-Esperanza Cerdán

Biomolecules 2022, 12(2), 319; https://doi.org/10.3390/biom12020319 - 17 Feb 2022

Cited by 1 | Viewed by 1330

High Mobility Group (HMG) proteins are today the focus of interest due to their participation in human degenerative diseases and inflammatory responses [...] Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

Research

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16 pages, 3573 KiB

Open AccessArticle

HMGB1 Inhibition to Ameliorate Organ Failure and Increase Survival in Trauma

by Zhangsheng Yang, Milomir O. Simovic, Peter R. Edsall, Bin Liu, Tomas S. Cancio, Andriy I. Batchinsky, Leopoldo C. Cancio and Yansong Li

Biomolecules 2022, 12(1), 101; https://doi.org/10.3390/biom12010101 - 08 Jan 2022

Cited by 13 | Viewed by 1860

Abstract

Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators [...] Read more.

Several preclinical and clinical reports have demonstrated that levels of circulating high mobility group box 1 protein (HMGB1) are increased early after trauma and are associated with systemic inflammation and clinical outcomes. However, the mechanisms of the interaction between HMGB1 and inflammatory mediators that lead to the development of remote organ damage after trauma remain obscure. HMGB1 and inflammatory mediators were analyzed in plasma from 54 combat casualties, collected on admission to a military hospital in Iraq, and at 8 and 24 h after admission. In total, 45 (83%) of these patients had traumatic brain injury (TBI). Nine healthy volunteers were enrolled as controls. HMGB1 plasma levels were significantly increased in the first 8 h after admission, and were found to be associated with systemic inflammatory responses, injury severity score, and presence of TBI. These data provided the rationale for designing experiments in rats subjected to blast injury and hemorrhage, to explore the effect of HMGB1 inhibition by CX-01 (2-O, 3-O desulfated heparin). Animals were cannulated, then recovered for 5–7 days before blast injury in a shock tube and volume-controlled hemorrhage. Blast injury and hemorrhage induced an early increase in HMGB1 plasma levels along with severe tissue damage and high mortality. CX-01 inhibited systemic HMGB1 activity, decreased local and systemic inflammatory responses, significantly reduced tissue and organ damage, and tended to increase survival. These data suggest that CX-01 has potential as an adjuvant treatment for traumatic hemorrhage. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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20 pages, 4946 KiB

Open AccessArticle

The HMGB Protein KlIxr1, a DNA Binding Regulator of Kluyveromyces lactis Gene Expression Involved in Oxidative Metabolism, Growth, and dNTP Synthesis

by Agustín Rico-Díaz, Aída Barreiro-Alonso, Cora Rey-Souto, Manuel Becerra, Mónica Lamas-Maceiras, M. Esperanza Cerdán and Ángel Vizoso-Vázquez

Biomolecules 2021, 11(9), 1392; https://doi.org/10.3390/biom11091392 - 21 Sep 2021

Cited by 2 | Viewed by 2378

Abstract

In the traditional fermentative model yeast Saccharomyces cerevisiae, ScIxr1 is an HMGB (High Mobility Group box B) protein that has been considered as an important regulator of gene transcription in response to external changes like oxygen, carbon source, or nutrient availability. [...] Read more.

In the traditional fermentative model yeast Saccharomyces cerevisiae, ScIxr1 is an HMGB (High Mobility Group box B) protein that has been considered as an important regulator of gene transcription in response to external changes like oxygen, carbon source, or nutrient availability. Kluyveromyces lactis is also a useful eukaryotic model, more similar to many human cells due to its respiratory metabolism. We cloned and functionally characterized by different methodologies KlIXR1, which encodes a protein with only 34.4% amino acid sequence similarity to ScIxr1. Our data indicate that both proteins share common functions, including their involvement in the response to hypoxia or oxidative stress induced by hydrogen peroxide or metal treatments, as well as in the control of key regulators for maintenance of the dNTP (deoxyribonucleotide triphosphate) pool and ribosome synthesis. KlIxr1 is able to bind specific regulatory DNA sequences in the promoter of its target genes, which are well conserved between S. cerevisiae and K. lactis. Oppositely, we found important differences between ScIrx1 and KlIxr1 affecting cellular responses to cisplatin or cycloheximide in these yeasts, which could be dependent on specific and non-conserved domains present in these two proteins. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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18 pages, 6738 KiB

Open AccessFeature PaperArticle

Disulfide and Fully Reduced HMGB1 Induce Different Macrophage Polarization and Migration Patterns

by Henna Salo, Heshuang Qu, Dimitra Mitsiou, Hannah Aucott, Jinming Han, Xingmei Zhang, Cecilia Aulin and Helena Erlandsson Harris

Biomolecules 2021, 11(6), 800; https://doi.org/10.3390/biom11060800 - 28 May 2021

Cited by 12 | Viewed by 3872

Abstract

Macrophage plasticity enables cells to obtain different functions over a broad proinflammatory and repairing spectrum. In different conditions, macrophages can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates innate immunity, to polarize towards a pro- (M1) or [...] Read more.

Macrophage plasticity enables cells to obtain different functions over a broad proinflammatory and repairing spectrum. In different conditions, macrophages can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates innate immunity, to polarize towards a pro- (M1) or anti-inflammatory (M2) phenotype. In this study, we investigated the phenotypes of murine bone-marrow-derived macrophages (BMDMs) induced by different HMGB1 redox isoforms in depth. Our results demonstrate that disulfide HMGB1 (dsHMGB1) induces a unique macrophage phenotype that secretes pro-inflammatory cytokines, rather than inducing metabolic changes leading to nitric oxide production. Fully reduced HMGB1 (frHMGB1) did not induce macrophage polarization. The migrating function of BMDMs was measured by scratch assay after the stimulation with dsHMGB1 and frHMGB1. Both dsHMGB1 and frHMGB1 induced cell migration. We found that dsHMGB1 mediates cytokine secretion and cellular motility, mainly through toll-like receptor 4 (TLR4). Importantly, our data shows that dsHMGB1 and frHMGB1 induce distinct BMDM polarization phenotypes, and that dsHMGB1 induces a unique phenotype differing from the classical proinflammatory macrophage phenotype. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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24 pages, 9254 KiB

Open AccessArticle

Nonhistone Proteins HMGB1 and HMGB2 Differentially Modulate the Response of Human Embryonic Stem Cells and the Progenitor Cells to the Anticancer Drug Etoposide

by Alireza Jian Bagherpoor, Martin Kučírek, Radek Fedr, Soodabeh Abbasi Sani and Michal Štros

Biomolecules 2020, 10(10), 1450; https://doi.org/10.3390/biom10101450 - 15 Oct 2020

Cited by 5 | Viewed by 2695

Abstract

HMGB1 and HMGB2 proteins are abundantly expressed in human embryonic stem cells
(hESCs) and hESC-derived progenitor cells (neuroectodermal cells, hNECs), though their functional
roles in pluripotency and the mechanisms underlying their dierentiation in response to the anticancer
drug etoposide remain to be elucidated. [...] Read more.

HMGB1 and HMGB2 proteins are abundantly expressed in human embryonic stem cells
(hESCs) and hESC-derived progenitor cells (neuroectodermal cells, hNECs), though their functional
roles in pluripotency and the mechanisms underlying their dierentiation in response to the anticancer
drug etoposide remain to be elucidated. Here, we show that HMGB1 and/or HMGB2 knockdown
(KD) by shRNA in hESCs did not aect the cell stemness/pluripotency regardless of etoposide
treatments, while in hESC-derived neuroectodermal cells, treatment resulted in dierential eects on
cell survival and the generation of rosette structures. The objective of this work was to determine
whether HMGB1/2 proteins could modulate the sensitivity of hESCs and hESC-derived progenitor
cells (hNECs) to etoposide. We observed that HMGB1 KD knockdown (KD) and, to a lesser extent,
HMGB2 KD enhanced the sensitivity of hESCs to etoposide. Enhanced accumulation of 53BP1 on
telomeres was detected by confocal microscopy in both untreated and etoposide-treated HMGB1
KD hESCs and hNECs, indicating that the loss of HMGB1 could destabilize telomeres. On the other
hand, decreased accumulation of 53BP1 on telomeres in etoposide-treated HMGB2 KD hESCs
(but not in HMGB2 KD hNECs) suggested that the loss of HMGB2 promoted the stability of telomeres.
Etoposide treatment of hESCs resulted in a significant enhancement of telomerase activity, with
the highest increase observed in the HMGB2 KD cells. Interestingly, no changes in telomerase activity
were found in etoposide-treated control hNECs, but HMGB2 KD (unlike HMGB1 KD) markedly
decreased telomerase activity in these cells. Changes in telomerase activity in the etoposide-treated
HMGB2 KD hESCs or hNECs coincided with the appearance of DNA damage markers and could
already be observed before the onset of apoptosis. Collectively, we have demonstrated that HMGB1
or HMGB2 dierentially modulate the impact of etoposide treatment on human embryonic stem cells
and their progenitor cells, suggesting possible strategies for the enhancement of the ecacy of this
anticancer drug. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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Review

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14 pages, 722 KiB

Open AccessEditor’s ChoiceReview

Interactions of HMGB Proteins with the Genome and the Impact on Disease

by Calvin K. Voong, James A. Goodrich and Jennifer F. Kugel

Biomolecules 2021, 11(10), 1451; https://doi.org/10.3390/biom11101451 - 02 Oct 2021

Cited by 25 | Viewed by 3821

Abstract

High Mobility Group Box (HMGB) proteins are small architectural DNA binding proteins that regulate multiple genomic processes such as DNA damage repair, nucleosome sliding, telomere homeostasis, and transcription. In doing so they control both normal cellular functions and impact a myriad of disease [...] Read more.

High Mobility Group Box (HMGB) proteins are small architectural DNA binding proteins that regulate multiple genomic processes such as DNA damage repair, nucleosome sliding, telomere homeostasis, and transcription. In doing so they control both normal cellular functions and impact a myriad of disease states, including cancers and autoimmune diseases. HMGB proteins bind to DNA and nucleosomes to modulate the local chromatin environment, which facilitates the binding of regulatory protein factors to the genome and modulates higher order chromosomal organization. Numerous studies over the years have characterized the structure and function of interactions between HMGB proteins and DNA, both biochemically and inside cells, providing valuable mechanistic insight as well as evidence these interactions influence pathological processes. This review highlights recent studies supporting the roles of HMGB1 and HMGB2 in global organization of the genome, as well as roles in transcriptional regulation and telomere maintenance via interactions with G-quadruplex structures. Moreover, emerging models for how HMGB proteins function as RNA binding proteins are presented. Nuclear HMGB proteins have broad regulatory potential to impact numerous aspects of cellular metabolism in normal and disease states. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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14 pages, 1989 KiB

Open AccessReview

HMGA1, Moonlighting Protein Function, and Cellular Real Estate: Location, Location, Location!

by Mireia Pujals, Linda Resar and Josep Villanueva

Biomolecules 2021, 11(9), 1334; https://doi.org/10.3390/biom11091334 - 09 Sep 2021

Cited by 7 | Viewed by 3127

Abstract

The gene encoding the High Mobility Group A1 (HMGA1) chromatin remodeling protein is upregulated in diverse cancers where high levels portend adverse clinical outcomes. Until recently, HMGA1 was assumed to be a nuclear protein exerting its role in cancer by transcriptionally modulating gene [...] Read more.

The gene encoding the High Mobility Group A1 (HMGA1) chromatin remodeling protein is upregulated in diverse cancers where high levels portend adverse clinical outcomes. Until recently, HMGA1 was assumed to be a nuclear protein exerting its role in cancer by transcriptionally modulating gene expression and downstream signaling pathways. However, the discovery of an extracellular HMGA1-RAGE autocrine loop in invasive triple-negative breast cancer (TNBC) cell lines implicates HMGA1 as a “moonlighting protein” with different functions depending upon cellular location. Here, we review the role of HMGA1, not only as a chromatin regulator in cancer and stem cells, but also as a potential secreted factor that drives tumor progression. Prior work found that HMGA1 is secreted from TNBC cell lines where it signals through the receptor for advanced glycation end products (RAGE) to foster phenotypes involved in tumor invasion and metastatic progression. Studies in primary TNBC tumors also suggest that HMGA1 secretion associates with distant metastasis in TNBC. Given the therapeutic potential to target extracellular proteins, further work to confirm this role in other contexts is warranted. Indeed, crosstalk between nuclear and secreted HMGA1 could change our understanding of tumor development and reveal novel therapeutic opportunities relevant to diverse human cancers overexpressing HMGA1. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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12 pages, 2173 KiB

Open AccessReview

HMGA1 Is a Potential Driver of Preeclampsia Pathogenesis by Interference with Extravillous Trophoblasts Invasion

by Keiichi Matsubara, Yuko Matsubara, Yuka Uchikura, Katsuko Takagi, Akiko Yano and Takashi Sugiyama

Biomolecules 2021, 11(6), 822; https://doi.org/10.3390/biom11060822 - 31 May 2021

Cited by 8 | Viewed by 3293

Abstract

Preeclampsia (PE) is a serious disease that can be fatal for the mother and fetus. The two-stage theory has been proposed as its cause, with the first stage comprising poor placentation associated with the failure of fertilized egg implantation. Successful implantation and placentation [...] Read more.

Preeclampsia (PE) is a serious disease that can be fatal for the mother and fetus. The two-stage theory has been proposed as its cause, with the first stage comprising poor placentation associated with the failure of fertilized egg implantation. Successful implantation and placentation require maternal immunotolerance of the fertilized egg as a semi-allograft and appropriate extravillous trophoblast (EVT) invasion of the decidua and myometrium. The disturbance of EVT invasion during implantation in PE results in impaired spiral artery remodeling. PE is thought to be caused by hypoxia during remodeling failure–derived poor placentation, which results in chronic inflammation. High-mobility group protein A (HMGA) is involved in the growth and invasion of cancer cells and likely in the growth and invasion of trophoblasts. Its mechanism of action is associated with immunotolerance. Thus, HMGA is thought to play a pivotal role in successful pregnancy, and its dysfunction may be related to the pathogenesis of PE. The evaluation of HMGA function and its changes in PE might confirm that it is a reliable biomarker of PE and provide prospects for PE treatment through the induction of EVT proliferation and invasion during the implantation. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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36 pages, 1810 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial HMG-Box Containing Proteins: From Biochemical Properties to the Roles in Human Diseases

by Veronika Vozáriková, Nina Kunová, Jacob A. Bauer, Ján Frankovský, Veronika Kotrasová, Katarína Procházková, Vladimíra Džugasová, Eva Kutejová, Vladimír Pevala, Jozef Nosek and Ľubomír Tomáška

Biomolecules 2020, 10(8), 1193; https://doi.org/10.3390/biom10081193 - 16 Aug 2020

Cited by 13 | Viewed by 4600

Abstract

Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression [...] Read more.

Mitochondrial DNA (mtDNA) molecules are packaged into compact nucleo-protein structures called mitochondrial nucleoids (mt-nucleoids). Their compaction is mediated in part by high-mobility group (HMG)-box containing proteins (mtHMG proteins), whose additional roles include the protection of mtDNA against damage, the regulation of gene expression and the segregation of mtDNA into daughter organelles. The molecular mechanisms underlying these functions have been identified through extensive biochemical, genetic, and structural studies, particularly on yeast (Abf2) and mammalian mitochondrial transcription factor A (TFAM) mtHMG proteins. The aim of this paper is to provide a comprehensive overview of the biochemical properties of mtHMG proteins, the structural basis of their interaction with DNA, their roles in various mtDNA transactions, and the evolutionary trajectories leading to their rapid diversification. We also describe how defects in the maintenance of mtDNA in cells with dysfunctional mtHMG proteins lead to different pathologies at the cellular and organismal level. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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