HMGB1

Key takeaways

HMGB1 belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect HMGB1 to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of HMGB1 from memory before moving on to harder problems.

Reference excerpt

High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene. HMG-1 belongs to the high mobility group and contains a HMG-box domain.

Function Like the histones, HMGB1 is among the most important chromatin proteins. In the nucleus HMGB1 interacts with nucleosomes, transcription factors, and histones. This nuclear protein organizes the DNA and regulates transcription. After binding, HMGB1 bends DNA, which facilitates the binding of other proteins. HMGB1 supports transcription of many genes in interactions with many transcription factors. It also interacts with nucleosomes to loosen packed DNA and remodel the chromatin. Contact with core histones changes the structure of nucleosomes. The presence of HMGB1 in the nucleus depends on posttranslational modifications. When the protein is not acetylated, it stays in the nucleus, but hyperacetylation on lysine residues causes it to translocate into the cytosol. HMGB1 has been shown to play an important role in helping the RAG endonuclease form a paired complex during V(D)J recombination.

Role in inflammation HMGB1 is secreted by immune cells (e.g. macrophages, monocytes and dendritic cells) through leaderless secretory pathway. Activated macrophages and monocytes secrete HMGB1 as a cytokine mediator of inflammation. Antibodies that neutralize HMGB1 confer protection against damage and tissue injury during arthritis, colitis, ischemia, sepsis, endotoxemia, and systemic lupus erythematosus. The mechanism of inflammation and damage consists of binding to toll-like receptor TLR2 and TLR4, which mediates HMGB1-dependent activation of macrophage cytokine release. This positions HMGB1 at the intersection of sterile and infectious inflammatory responses. ADP-ribosylation of HMGB1 by PARP1 inhibits removal of apoptotic cells, thereby sustaining inflammation. TLR4 binding by HMGB1 or lipopolysaccharide (LPS) sustains ADP-ribosylation of HMGB1 by PARP1 thereby serving as an amplification loop for inflammation. HMGB1 has been proposed as a DNA vaccine adjuvant. HMGB1 released from tumour cells was demonstrated to mediate anti-tumour immune responses by activating toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs.

Interactions HMGB1 has to interact with p53. HMGB1 is a nuclear protein that binds to DNA and acts as an architectural chromatin-binding factor. It can also be released from cells, an extracellular form in which it may bind to toll-like receptors (TLRs) or an inflammatory receptor called the receptor for advanced glycation end-products RAGE. Release from cells seems to involve two distinct processes: necrosis, in which case cell membranes are permeabilized and intracellular constituents may diffuse out of the cell; and some form of active or facilitated secretion induced by signaling through the NF-κB. HMGB1 also translocates to the cytosol under stressful conditions such as increased ROS inside the cells. Under such conditions, HMGB1 promotes cell survival by sustaining autophagy through interactions with beclin-1. It is largely considered as an antiapoptotic protein. HMGB1 can interact with TLR ligands and cytokines, and activates cells through the multiple surface receptors including TLR2, TLR4, and RAGE.

Interaction via TLR4 Some actions of HMGB1 are mediated through the toll-like receptors (TLRs). Interaction between HMGB1 and TLR4 results in upregulation of NF-κB, which leads to increased production and release of cytokines. HMGB1 is also able to interact with TLR4 on neutrophils to stimulate the production of reactive oxygen species by NADPH oxidase. HMGB1-LPS complex activates TLR4, and causes the binding of adapter proteins (MyD88 and others), leading to signal transduction and the activation of various signaling cascades. The downstream effect of this signaling is to activate MAPK and NF-κB, and thus cause the production of inflammatory molecules such as cytokines.

Clinical significance HMGB1 has been proposed as a target for cancer therapy, as well as a vector for reducing inflammation from SARS-CoV-2 infection. It also serves as a biomarker for post-COVID-19 condition. The neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) is caused by mutation in the ataxin 1 gene. In a mouse model of SCA1, mutant ataxin 1 protein mediated the reduction or inhibition of HMGB1 in the mitochondria of neurons. HMGB1 regulates DNA architectural changes essential for repair of DNA damage. In the SCA1 mouse model, over-expression of the HMGB1 protein by means of an introduced virus vector bearing the HMGB1 gene facilitated repair of the mitochondrial DNA damage, ameliorated the neuropathology and the motor defects of the SCA1 mice, and also extended their lifespan. Thus impairment of HMGB1 function appears to have a key role in the pathogenesis of SCA1. Recently, a study provided evidence of an association between raised levels of HMGB1 and attention to detail and systemizing in unmedicated children with high-functioning autism spectrum disorder (ASD), suggesting that inflammatory processes mediated by HMGB1 may play a role in the disruption of neurobiological mechanisms regulating cognitive processes in ASD. In this study, HMGB1 serum concentrations in children with ASD were found significantly higher than those of typically developing children. Additionally, HMGB1 serum concentrations were positively correlated with the Autistic quotient (AQ) attention to detail score and the Systemizing Quotient (SQ) total score in the ASD group. However, comprehensive evidence in children is limited, highlighting the need for in-depth research towards understanding possible mechanisms linking HMGB1 with the core features of ASD. Nevertheless, it has been suggested that HMGB1 could be a reliable inflammatory marker, explaining the link between inflammatory processes and several autistic traits, and therefore a possible therapeutic target in this neurodevelopmental disorder.

References

Illustrations

Worked examples

Example 1 — a first encounter with HMGB1

Start with the simplest possible case. Write down what HMGB1 claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to HMGB1 before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about HMGB1 ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of HMGB1

In research: HMGB1 appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses HMGB1 in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: HMGB1 is common in secondary-school and first-year university syllabi. It links to neighbouring topics Genes on human chromosome 13, Transcription factors, so understanding it makes those chapters shorter.
In everyday life: Look for HMGB1 outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

How to study HMGB1 in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what HMGB1 means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain HMGB1 out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is HMGB1 in simple terms?

High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene. HMG-1 belongs to the high mobility group and contains a HMG-box domain.

Why does HMGB1 matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study HMGB1?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on HMGB1.