Biology:Rubicon (protein)

From HandWiki
Short description: Human protein involved in autophagy regulation


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Rubicon (run domain Beclin-1-interacting and cysteine-rich domain-containing protein) is a protein that in humans is encoded by the RUBCN gene.[1][2] Rubicon is one of the few known negative regulators of autophagy, a cellular process that degrades unnecessary or damaged cellular components.[3] Rubicon is recruited to its sites of action through interaction with the small GTPase Rab7,[3][4] and impairs the autophagosome-lysosome fusion step of autophagy through inhibition of PI3KC3-C2 (class III phosphatidylinositol 3-kinase complex 2).[3][5]

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,[6] and in mice decreases kidney fibrosis and α-synuclein accumulation.[6]

In addition to regulation of autophagy, Rubicon has been shown to be required for LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO).[7][8] Rubicon has also been shown to negatively regulate the innate immune response through direct interaction with multiple downstream regulatory molecules.[9][10][11]

Structure

X-ray crystal structure of human Rubicon RH domain (red) bound to Rab7-GTP (grey) (PDB ID: 6WCW).[3]

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.[12]

The Rubicon homology domain is rich in cysteine residues and binds at least 4 divalent Zinc ions, forming zinc finger motifs.[3] The structural basis for interaction between Rubicon and GTP-bound Rab7 has been experimentally determined (PDB ID: 6WCW).[3][13]

Function

The function of the N-terminal RUN domain are unknown, but it is required for autophagy suppression.[14] The middle region contains the PI3K-binding domain (PIKBD), which mediates inhibition of PI3KC3-C2.[5] 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).[3]

Autophagy-dependent

Rubicon suppresses autophagy through association with and inhibition of PI3KC3-C2.[15] Specifically, Rubicon directly binds PI3KC3-C2[16][1] and inhibits recruitment of PI3KC3-C2 to the membrane through conformational modulation of the Beclin-1 subunit.[5] 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.[5] Rubicon is targeted to its site of action through direct interaction with Rab7, which decorates late endosomes and late autophagosomes.[3][4]

Autophagy-independent

Rubicon is required for LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO).[7][8] 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.[7]

Rubicon has been shown to suppress the innate immune response and in some cases exacerbate viral replication.[9] Rubicon suppresses cytokine responses through interaction with NF-κB essential modulator (NEMO),[9] interferon regulatory factor 3 (IRF3)[11] and caspase recruitment domain-containing protein 9 (CARD9).[10]

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.[6] Since reduced autophagy is associated with aging and age-related diseases, modulation of Rubicon has been identified as a potential therapeutic target.[3][5]

In mice, Rubicon knockout reduces α-synuclein accumulation in the brain and reduces interstitial fibrosis in the kidney.[6]

Aging

Rubicon knockout increases lifespan in roundworms (C. elegans) through modulation of autophagy, and also increases lifespan in female fruit flies (D. melanogaster).[6]

Nonalcoholic fatty liver disease (NAFLD)

Rubicon levels are increased in mouse models of nonalcoholic fatty liver disease (NAFLD).[17] Knockout of Rubicon in hepatocytes improves liver steatosis and autophagy, suggesting that Rubicon contributes to NAFLD pathogenesis.[17]

Metabolic disease

Age-dependent decline of Rubicon expression in adipose tissues may exacerbate metabolic disorders due to excessive autophagic activity.[18]

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.[19] 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.[20] The resulting disruption of the C-terminal domain impairs Rubicon subcellular localization with Rab7 and late endosomes.[21]

See also

References

  1. ↑ 1.0 1.1 "Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex". Nature Cell Biology 11 (4): 468–476. April 2009. doi:10.1038/ncb1854. PMID 19270693. 
  2. ↑ "RUBCN - Run domain Beclin-1-interacting and cysteine-rich domain-containing protein - Homo sapiens (Human) - RUBCN gene & protein" (in en). https://www.uniprot.org/uniprot/Q92622. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex". Proceedings of the National Academy of Sciences of the United States of America 117 (29): 17003–17010. July 2020. doi:10.1073/pnas.2008030117. PMID 32632011. Bibcode: 2020PNAS..11717003B. 
  4. ↑ 4.0 4.1 "Rubicon and PLEKHM1 negatively regulate the endocytic/autophagic pathway via a novel Rab7-binding domain". Molecular Biology of the Cell 21 (23): 4162–4172. December 2010. doi:10.1091/mbc.E10-06-0495. PMID 20943950. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics". Molecular Cell 73 (2): 339–353.e6. January 2019. doi:10.1016/j.molcel.2018.10.035. PMID 30581147. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Suppression of autophagic activity by Rubicon is a signature of aging". Nature Communications 10 (1): 847. February 2019. doi:10.1038/s41467-019-08729-6. PMID 30783089. 
  7. ↑ 7.0 7.1 7.2 "Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins". Nature Cell Biology 17 (7): 893–906. July 2015. doi:10.1038/ncb3192. PMID 26098576. 
  8. ↑ 8.0 8.1 "LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease". Cell 178 (3): 536–551.e14. July 2019. doi:10.1016/j.cell.2019.05.056. PMID 31257024. 
  9. ↑ 9.0 9.1 9.2 "Rubicon: a facilitator of viral immune evasion". Cellular & Molecular Immunology 16 (9): 770–771. September 2019. doi:10.1038/s41423-019-0248-7. PMID 31164715. 
  10. ↑ 10.0 10.1 "The autophagy regulator Rubicon is a feedback inhibitor of CARD9-mediated host innate immunity". Cell Host & Microbe 11 (3): 277–289. March 2012. doi:10.1016/j.chom.2012.01.019. PMID 22423967. 
  11. ↑ 11.0 11.1 "Rubicon Modulates Antiviral Type I Interferon (IFN) Signaling by Targeting IFN Regulatory Factor 3 Dimerization". Journal of Virology 91 (14): e00248–17. July 2017. doi:10.1128/JVI.00248-17. PMID 28468885. 
  12. ↑ "RUBCN - Run domain Beclin-1-interacting and cysteine-rich domain-containing protein - Homo sapiens (Human) - RUBCN gene & protein" (in en). https://www.uniprot.org/uniprot/Q92622. 
  13. ↑ "RCSB PDB - 6WCW: Structure of human Rubicon RH domain in complex with GTP-bound Rab7" (in en-US). RCSB Protein Data Bank. https://www.rcsb.org/structure/6wcw. 
  14. ↑ "The RUN domain of rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression". The Journal of Biological Chemistry 286 (1): 185–191. January 2011. doi:10.1074/jbc.M110.126425. PMID 21062745. 
  15. ↑ "Rubicon in Metabolic Diseases and Ageing". Frontiers in Cell and Developmental Biology 9: 816829. 2021. doi:10.3389/fcell.2021.816829. PMID 35083223. 
  16. ↑ "Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages". Nature Cell Biology 11 (4): 385–396. April 2009. doi:10.1038/ncb1846. PMID 19270696. 
  17. ↑ 17.0 17.1 "Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice". Hepatology 64 (6): 1994–2014. December 2016. doi:10.1002/hep.28820. PMID 27637015. 
  18. ↑ "Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy". Nature Communications 11 (1): 4150. August 2020. doi:10.1038/s41467-020-17985-w. PMID 32811819. Bibcode: 2020NatCo..11.4150Y. 
  19. ↑ "Spinocerebellar ataxia, autosomal recessive, 15". https://www.uniprot.org/diseases/DI-04054. 
  20. ↑ "Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia". Brain 133 (Pt 8): 2439–2447. August 2010. doi:10.1093/brain/awq181. PMID 20826435. 
  21. ↑ "The Salih ataxia mutation impairs Rubicon endosomal localization". Cerebellum 12 (6): 835–840. December 2013. doi:10.1007/s12311-013-0489-4. PMID 23728897. 




Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:Rubicon_(protein)&oldid=3638630"