Rubicon (protein)
Human protein involved in autophagy regulation
From Wikipedia, the free encyclopedia
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]
| 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; GeneCards: RUBCN | |||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Wikidata | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
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
Aging-related diseases
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]