AMBRA1 (activating molecule in Beclin1-regulated autophagy) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that is able to regulate

cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...

cells through

autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...

. AMBRA1 is described as a mechanism cells use to divide and there is new evidence demonstrating the role and impact of AMBRA1 as a candidate for the treatment of several disorders and diseases, including anticancer therapy. It is known to suppress tumors and plays a role in

mitophagy Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described in 1915 by Margaret Reed Lewis and Warren Harmon Lewis. Ashford ...

and

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

. AMBRA1 can be found in the

cytoskeleton The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...

and

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

and during the process of autophagy, it is localized at the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

. In normal conditions, AMBRA1 is dormant and will bind to

BCL2 Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the apoptosis regulator proteins, Bcl-2 family, Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can eithe ...

in the outer membrane. This relocation enables

autophagosome An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents (e.g., abnormal intracellular proteins, excess or damaged organelles, i ...

nucleation In thermodynamics, nucleation is the first step in the formation of either a new Phase (matter), thermodynamic phase or Crystal structure, structure via self-assembly or self-organization within a substance or mixture. Nucleation is typically def ...

. AMBRA1 protein is involved in several cellular processes and is involved in the regulation of the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

and

nervous system In biology, the nervous system is the complex system, highly complex part of an animal that coordinates its behavior, actions and sense, sensory information by transmitting action potential, signals to and from different parts of its body. Th ...

Function

AMBRA1 serves to regulate the process of autophagy and this is the cellular breakdown and recycling of unnecessary or damaged cellular components. This protein interacts with other proteins and genes to initiate the formation of autophagosomes, an essential component of autophagy. Cellular processes such as cell proliferation, apoptosis, and cellular metabolism are regulated through the interactions between AMBRA1 and other proteins. AMBRA1 is involved in regulating the cell cycle and it recognizes and binds to D-type cyclins which promotes

cell proliferation Cell proliferation is the process by which ''a cell grows and divides to produce two daughter cells''. Cell proliferation leads to an exponential increase in cell number and is therefore a rapid mechanism of tissue growth. Cell proliferation ...

. This leads to cyclin-D degradation where AMBRA1 suppresses tumors, prevents their growth, and promotes genetic integrity. AMBRA1 is also known to mediate polyubiquitylation of several proteins. Bartolomeo et al. demonstrated AMBRA1 signals the motor complex to initiate autophagy when it is released from microtubules. Through autophagy, cellular homeostasis is maintained, and the buildup of toxic or damaged proteins is prevented. Reynolds(2021) shows the repercussions of the loss of AMBRA1, which can no longer control the cell cycle from uncontrolled cell division and growth. One of the interactions AMBRA1 has with Beclin1 aids in

and protein replacement during neural development. AMBRA1 is able to promote activity in

PIK3C3 Phosphatidylinositol 3-kinase catalytic subunit type 3 is an enzyme subunit that in humans is encoded by the ''PIK3C3'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is ...

, increase

kinase In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...

activity during autophagy, and activate ULK1. AMBRA1 promotes

FOXO3 Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the ''FOXO3'' gene. Function FOXO3 belongs to the O subclass of the forkhead family of transcription factors which are characterized by a distinct fork head DNA- ...

and Nazio et al. (2021) showed when AMBRA1 is reduced, there is inhibition of STAT3 signaling which reduces the regulation of innate and adaptive immunity. In addition, AMBRA1 is an essential component for STAT3 signaling as FOXO3 regulates gene expression in autophagy.

Mechanism

The exact mechanisms of this protein are not yet fully understood. Several processes including autophagy and apoptosis are some that AMBRA1 is involved with. Through the formation of

s, structures that engulf cellular components to break them down, autophagy is initiated. AMBRA1 regulates the activity of the mTORC1 complex and this complex serves as a regulator of cell metabolism and growth. Apart from autophagy, AMBRA1 plays an essential role in apoptosis and cell proliferation. For enabling cell death, the

p53 p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...

pathway is activated and this is done upon the release of cytochrome C from

. AMBRA1 has been a topic of research for anti-cancer therapies through the regulation of the immune system. AMBRA1 is additionally involved in the development of the nervous system through the regulation of biological processes involving

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

and other neurodegenerative disorders.

Interactions

Simoneschi et al. demonstrated that there is an interaction between AMBRA1 and the cyclin-D pathway. D-type cyclins activate

CDK4 Cyclin-dependent kinase 4 (CDK4), also known as cell division protein kinase 4, is an enzyme that is encoded by the ''CDK4'' gene in humans. CDK4 is a member of the cyclin-dependent kinase family, a group of serine/threonine kinases which regula ...

and

CDK6 Cell division protein kinase 6 (CDK6) is an enzyme encoded by the ''CDK6'' gene. It is regulated by cyclins, more specifically by Cyclin D proteins and Cyclin-dependent kinase inhibitor proteins. The protein encoded by this gene is a member of t ...

and AMBRA1 protein targets these cyclins for degradation. The decrease in AMBRA1 proteins showed the prevention of polyubiquitylation of

cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lo ...

. The interactions provide evidence that AMBRA1 plays a role in the regulation of different cellular processes such as autophagy, cell proliferation, apoptosis, and

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

. AMBRA1 interacts with Beclin1 and ULK1 to initiate autophagy and form

s. The interaction with ULK1 also regulates cell proliferation. AMBRA1 interacts with

Bcl2 Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the apoptosis regulator proteins, Bcl-2 family, Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can eithe ...

and mito-and this aids in regulating and promoting apoptosis. There is a correlation between apoptosis and autophagy where AMBRA1 is released from

when autophagy takes place. This process increases Beclin1 activity and Strappazzon et al. found that the interactions are reduced during apoptosis. When AMBRA1 interacts with DLC1, a complex associated with

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

, the complex is moved to the

and the complex is harnessed to the cytoskeleton. AMBRA1 also interacts with the protein phosphatase 2A (PPP2CA) and this promotes MYC dephosphorylation and degradation.

MYC ''Myc'' is a family of regulator genes and proto-oncogenes that code for transcription factors. The ''Myc'' family consists of three related human genes: ''c-myc'' ( MYC), ''l-myc'' ( MYCL), and ''n-myc'' ( MYCN). ''c-myc'' (also sometimes r ...

is an oncogene and when degraded, it results in tumor suppression. The interactions with AMBRA1 and other proteins suggest the importance of AMBRA1 in cellular processes.

Clinical significance

AMBRA1 is clinically significant due to the importance of this

in cellular processes such as apoptosis and cell proliferation. Diseases such as

, neurodegenerative disorders and autoimmune diseases can arise. Frias et al., through studies concluded that the deletion of AMBRA1 results in the inhibition of tumors and

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

and reduced cytokine-mediated signaling. Tumorigenisis and tumor proliferation takes place when AMBRA1 fails to interact and promote the degradation of cyclin D. Diseases such as

Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

, and

Huntington's disease Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly Genetic disorder#Autosomal dominant, inherited. It typically presents as a triad of progressive psychiatric, cognitive, and ...

contain autophagy alterations. AMBRA1 plays a role in the development of Parkinson's disease and in interacting with Parkin, an E3 ubiquitin ligase, there is inhibition of Parkin mitophagy. AMBRA1 is involved in the regulation of the immune system and upcoming research demonstrates this protein might play a role in the development of

autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...

s since AMBRA1 is involved in autophagy. Understanding the functions of AMBRA1 and the role it plays in disease pathogenesis provide insight into the development of new treatment and therapies for the listed disorders.

References

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