Rubicon (protein)

Last updated
RUBCN
Identifiers
Aliases RUBCN , RUBICON, SCAR15, KIAA0226, RUN and cysteine rich domain containing beclin 1 interacting protein, rubicon autophagy regulator
External IDs OMIM: 613516; MGI: 1915160; HomoloGene: 15687; GeneCards: RUBCN; OMA:RUBCN - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001145642
NM_014687
NM_001346873

NM_001200038
NM_172615
NM_001374776

RefSeq (protein)

NP_001139114
NP_001333802
NP_055502

NP_001186967
NP_766203
NP_001361705

Location (UCSC) Chr 3: 197.67 – 197.75 Mb Chr 16: 32.64 – 32.7 Mb
PubMed search [3] [4]
Wikidata
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Rubicon (run domain Beclin-1-interacting and cysteine-rich domain-containing protein) is a protein that in humans is encoded by the RUBCN gene. [5] [6] Rubicon is one of the few known negative regulators of autophagy, a cellular process that degrades unnecessary or damaged cellular components. [7] Rubicon is recruited to its sites of action through interaction with the small GTPase Rab7, [7] [8] and impairs the autophagosome-lysosome fusion step of autophagy through inhibition of PI3KC3-C2 (class III phosphatidylinositol 3-kinase complex 2). [7] [9]

Contents

Negative modulation of Rubicon is associated with reduction of aging and aging-associated diseases: knockout of Rubicon increases lifespan in roundworms and female fruit flies, [10] and in mice decreases kidney fibrosis and α-synuclein accumulation. [10]

In addition to regulation of autophagy, Rubicon has been shown to be required for LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO). [11] Rubicon has also been shown to negatively regulate the innate immune response through direct interaction with multiple downstream regulatory molecules. [12] [13] [14]

Structure

X-ray crystal structure of human Rubicon RH domain (red) bound to Rab7-GTP (grey) (PDB ID: 6WCW). Crystal structure of Human Rubicon protein bound to Rab7-GTP.png
X-ray crystal structure of human Rubicon RH domain (red) bound to Rab7-GTP (grey) (PDB ID: 6WCW).

Rubicon consists of 972 amino acids and has an N-terminal RUN domain, a middle region (MR), and a C-terminal Rubicon homology (RH) domain. [15]

The Rubicon homology domain is rich in cysteine residues and binds at least 4 divalent Zinc ions, forming zinc finger motifs. [7] The structural basis for interaction between Rubicon and GTP-bound Rab7 has been experimentally determined (PDB ID: 6WCW). [7] [16]

Function

The function of the N-terminal RUN domain are unknown, but it is required for autophagy suppression. [17] The middle region contains the PI3K-binding domain (PIKBD), which mediates inhibition of PI3KC3-C2. [9] The C-terminal Rubicon homology domain mediates interaction with Rab7, and is shared by other RH domain-containing autophagy regulatory proteins, including PLEKHM1 and Pacer (also known as RUBCNL, Rubicon-like Autophagy Enhancer). [7]

Autophagy-dependent

Rubicon suppresses autophagy through association with and inhibition of PI3KC3-C2. [18] Specifically, Rubicon directly binds PI3KC3-C2 [19] [5] and inhibits recruitment of PI3KC3-C2 to the membrane through conformational modulation of the Beclin-1 subunit. [9] This activity prevents PI3KC3-directed generation of phosphatidylinositol 3-phosphate (PI3P) at the autophagosome membrane, and a resulting failure to recruit machinery that directs autophagosome-lysosome fusion. [9] Rubicon is targeted to its site of action through direct interaction with Rab7, which decorates late endosomes and late autophagosomes. [7] [8]

Autophagy-independent

Rubicon has been shown to suppress the innate immune response and in some cases exacerbate viral replication. [12] Rubicon suppresses cytokine responses through interaction with NF-κB essential modulator (NEMO), [12] interferon regulatory factor 3 (IRF3) [14] and caspase recruitment domain-containing protein 9 (CARD9). [13]

Role in aging and disease

Rubicon expression levels increase with age in mice and other model organisms, suggesting that Rubicon may cause age-associated decrease of autophagy. [10] Since reduced autophagy is associated with aging and age-related diseases, modulation of Rubicon has been identified as a potential therapeutic target. [7] [9]

In mice, Rubicon knockout reduces α-synuclein accumulation in the brain and reduces interstitial fibrosis in the kidney. [10]

Aging

Rubicon knockout increases lifespan in roundworms (C. elegans) through modulation of autophagy, and also increases lifespan in female fruit flies (D. melanogaster). [10]

Nonalcoholic fatty liver disease (NAFLD)

Rubicon levels are increased in mouse models of nonalcoholic fatty liver disease (NAFLD). [20] Knockout of Rubicon in hepatocytes improves liver steatosis and autophagy, suggesting that Rubicon contributes to NAFLD pathogenesis. [20]

Metabolic disease

Age-dependent decline of Rubicon expression in adipose tissues may exacerbate metabolic disorders due to excessive autophagic activity. [21]

Salih ataxia (SCAR15)

A single nucleotide deletion mutation within Rubicon is the cause of Salih ataxia (OMIM ID: 615705). Salih ataxia (also known as spinocerebellar ataxia, autosomal recessive 15 or SCAR15) is a form of spinocerebellar ataxia characterized by progressive loss of coordination of hands, gait, speech, and eye movement. [22] The disease was discovered in children carrying a mutation (c.2624delC p.Ala875ValfsX146) causing a frameshift mutation and an erroneous open reading frame in the Rubicon-coding gene starting from Alanine 875. [23] The resulting disruption of the C-terminal domain impairs Rubicon subcellular localization with Rab7 and late endosomes. [24]

See also

Related Research Articles

<span class="mw-page-title-main">Autophagy</span> Process of cells digesting parts of themselves

Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.

mTOR Mammalian protein found in humans

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<span class="mw-page-title-main">Bafilomycin</span> Chemical compound

The bafilomycins are a family of macrolide antibiotics produced from a variety of Streptomycetes. Their chemical structure is defined by a 16-membered lactone ring scaffold. Bafilomycins exhibit a wide range of biological activity, including anti-tumor, anti-parasitic, immunosuppressant and anti-fungal activity. The most used bafilomycin is bafilomycin A1, a potent inhibitor of cellular autophagy. Bafilomycins have also been found to act as ionophores, transporting potassium K+ across biological membranes and leading to mitochondrial damage and cell death.

<span class="mw-page-title-main">AP2 adaptor complex</span>

The AP2 adaptor complex is a multimeric protein that works on the cell membrane to internalize cargo in clathrin-mediated endocytosis. It is a stable complex of four adaptins which give rise to a structure that has a core domain and two appendage domains attached to the core domain by polypeptide linkers. These appendage domains are sometimes called 'ears'. The core domain binds to the membrane and to cargo destined for internalisation. The alpha and beta appendage domains bind to accessory proteins and to clathrin. Their interactions allow the temporal and spatial regulation of the assembly of clathrin-coated vesicles and their endocytosis.

<span class="mw-page-title-main">BNIP3</span> Protein-coding gene in the species Homo sapiens

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 is a protein found in humans that is encoded by the BNIP3 gene.

<span class="mw-page-title-main">BECN1</span> Protein-coding gene in the species Homo sapiens

Beclin-1 is a protein that in humans is encoded by the BECN1 gene. Beclin-1 is a mammalian ortholog of the yeast autophagy-related gene 6 (Atg6) and BEC-1 in the C. elegans nematode. This protein interacts with either BCL-2 or PI3k class III, playing a critical role in the regulation of both autophagy and cell death.

<span class="mw-page-title-main">Autophagy protein 5</span> Protein-coding gene in the species Homo sapiens

Autophagy protein 5 (ATG5) is a protein that, in humans, is encoded by the ATG5 gene located on chromosome 6. It is an E3 ubi autophagic cell death. ATG5 is a key protein involved in the extension of the phagophoric membrane in autophagic vesicles. It is activated by ATG7 and forms a complex with ATG12 and ATG16L1. This complex is necessary for LC3-I conjugation to PE (phosphatidylethanolamine) to form LC3-II. ATG5 can also act as a pro-apoptotic molecule targeted to the mitochondria. Under low levels of DNA damage, ATG5 can translocate to the nucleus and interact with survivin.

<span class="mw-page-title-main">MAP1LC3B</span> Protein-coding gene in the species Homo sapiens

Microtubule-associated proteins 1A/1B light chain 3B is a protein that in humans is encoded by the MAP1LC3B gene. LC3 is a central protein in the autophagy pathway where it functions in autophagy substrate selection and autophagosome biogenesis. LC3 is the most widely used marker of autophagosomes.

<span class="mw-page-title-main">MAP1LC3A</span> Protein-coding gene in the species Homo sapiens

Microtubule-associated proteins 1A/1B light chain 3A is a protein that in humans is encoded by the MAP1LC3A gene. Two transcript variants encoding different isoforms have been found for this gene.

<span class="mw-page-title-main">ATG16L1</span> Protein-coding gene in the species Homo sapiens

Autophagy related 16 like 1 is a protein that in humans is encoded by the ATG16L1 gene. This protein is characterized as a subunit of the autophagy-related ATG12-ATG5/ATG16 complex and is essentially important for the LC3 (ATG8) lipidation and autophagosome formation. This complex localizes to the membrane and is released just before or after autophagosome completion.

<span class="mw-page-title-main">ATG12</span> Protein-coding gene in the species Homo sapiens

Autophagy related 12 is a protein that in humans is encoded by the ATG12 gene.

<span class="mw-page-title-main">ULK1</span> Enzyme found in humans

Serine/threonine-protein kinase ULK1 is an enzyme that in humans is encoded by the ULK1 gene.

<span class="mw-page-title-main">PLEKHM1</span> Protein-coding gene in the species Homo sapiens

Pleckstrin homology domain-containing family M member 1 also known as PLEKHM1 is a protein that in humans is encoded by the PLEKHM1 gene.

<span class="mw-page-title-main">ATG8</span> Protein in budding yeast

Autophagy-related protein 8 (Atg8) is a ubiquitin-like protein required for the formation of autophagosomal membranes. The transient conjugation of Atg8 to the autophagosomal membrane through a ubiquitin-like conjugation system is essential for autophagy in eukaryotes. Even though there are homologues in animals, this article mainly focuses on its role in lower eukaryotes such as Saccharomyces cerevisiae.

<span class="mw-page-title-main">Autophagosome</span> Cell biology structure

An autophagosome is a spherical structure with double layer membranes. It is the key structure in macroautophagy, the intracellular degradation system for cytoplasmic contents. After formation, autophagosomes deliver cytoplasmic components to the lysosomes. The outer membrane of an autophagosome fuses with a lysosome to form an autolysosome. The lysosome's hydrolases degrade the autophagosome-delivered contents and its inner membrane.

Chaperone-assisted selective autophagy is a cellular process for the selective, ubiquitin-dependent degradation of chaperone-bound proteins in lysosomes.

<span class="mw-page-title-main">Pacer (protein)</span> Protein-coding gene in the species Homo sapiens

Pacer is a protein that in humans is encoded by the RUBCNL gene. Pacer has been shown to increase cellular autophagy through regulation of PI3KC3.

<span class="mw-page-title-main">Rubicon homology domain</span> Rubicon homology protein domain

The Rubicon homology domain is an evolutionarily conserved protein domain of approximately 250 amino acids that mediates protein–protein interaction. RH domains are present in several human proteins involved in regulation of autophagy and endosomal trafficking. While not all RH domains have been characterized, those of human Rubicon and PLEKHM1 mediate interaction with the small GTPase Rab7, which is found on late endosomes and autophagosomes.

<span class="mw-page-title-main">AMBRA1</span> Protein-coding gene

AMBRA1 is a protein that is able to regulate cancer cells through autophagy. 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 and apoptosis. AMBRA1 can be found in the cytoskeleton and mitochondria and during the process of autophagy, it is localized at the endoplasmic reticulum. In normal conditions, AMBRA1 is dormant and will bind to BCL2 in the outer membrane. This relocation enables autophagosome nucleation. AMBRA1 protein is involved in several cellular processes and is involved in the regulation of the immune system and nervous system.

Atg8ylation is a process of conjugation of mammalian ATG8 proteins (mATG8s) to proteins or membranes. The process is akin to the ubiquitylation of diverse substrates by ubiquitin. There are six principal mATG8s: LC3A, LC3B, LC3C, GABARAP, GABARAPL1 and GABARAPL2. Together, they comprise a sub-class of ubiquitin-like molecules characterized by two N-terminal α-helices added to the ubiquitin core, which serve a dual role of forming a docking site for interacting proteins containing ATG8-interaction motifs and enhancing mATG8’s affinity for membranes.

References

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