Rubicon (protein)

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]

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][12] Rubicon has also been shown to negatively regulate the innate immune response through direct interaction with multiple downstream regulatory molecules.^[13][14][15]

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.^[16]

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][17]

Function

The function of the N-terminal RUN domain are unknown, but it is required for autophagy suppression.

Rubicon is required for LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO).[11]^[12] Rubicon plays a role in PI3KC3 localization to phagosomes, which is important for PI3P production at the membrane and recruitment of downstream effectors including NOX2.^[11]

Rubicon has been shown to suppress the innate immune response and in some cases exacerbate viral replication.^[13] Rubicon suppresses cytokine responses through interaction with NF-κB essential modulator (NEMO),^[13] interferon regulatory factor 3 (IRF3)^[15] and caspase recruitment domain-containing protein 9 (CARD9).^[14]

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

Age-dependent decline of Rubicon expression in adipose tissues may exacerbate metabolic disorders due to excessive autophagic activity.[22]

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

• PLEKHM1
• RUBCNL (Rubicon-like)
• RAB7A
• Beclin-1

References