Rubicon (protein) explained

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. 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).

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

In addition to regulation of autophagy, Rubicon has been shown to be required for LC3-associated phagocytosis (LAP) and LC3-associated endocytosis (LANDO).[6] Rubicon has also been shown to negatively regulate the innate immune response through direct interaction with multiple downstream regulatory molecules.[7] [8] [9]

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.[10]

The Rubicon homology domain is rich in cysteine residues and binds at least 4 divalent Zinc ions, forming zinc finger motifs. The structural basis for interaction between Rubicon and GTP-bound Rab7 has been experimentally determined (PDB ID: 6WCW).[11]

Function

The function of the N-terminal RUN domain are unknown, but it is required for autophagy suppression.[12] The middle region contains the PI3K-binding domain (PIKBD), which mediates inhibition of PI3KC3-C2.[13] 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).

Autophagy-dependent

Rubicon suppresses autophagy through association with and inhibition of PI3KC3-C2.[14] Specifically, Rubicon directly binds PI3KC3-C2[15] and inhibits recruitment of PI3KC3-C2 to the membrane through conformational modulation of the Beclin-1 subunit. 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. Rubicon is targeted to its site of action through direct interaction with Rab7, which decorates late endosomes and late autophagosomes.

Autophagy-independent

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

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

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

Aging

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

Nonalcoholic fatty liver disease (NAFLD)

Rubicon levels are increased in mouse models of nonalcoholic fatty liver disease (NAFLD).[16] Knockout of Rubicon in hepatocytes improves liver steatosis and autophagy, suggesting that Rubicon contributes to NAFLD pathogenesis.

Metabolic disease

Age-dependent decline of Rubicon expression in adipose tissues may exacerbate metabolic disorders due to excessive autophagic activity.[17]

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.[18] 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.[19] The resulting disruption of the C-terminal domain impairs Rubicon subcellular localization with Rab7 and late endosomes.[20]

See also

Notes and References

  1. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, Heintz N, Yue Z . 6 . 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 . 19270693 . 2664389 . 10.1038/ncb1854 .
  2. Web site: RUBCN - Run domain Beclin-1-interacting and cysteine-rich domain-containing protein - Homo sapiens (Human) - RUBCN gene & protein . 2022-05-30 . www.uniprot.org . en.
  3. Bhargava HK, Tabata K, Byck JM, Hamasaki M, Farrell DP, Anishchenko I, DiMaio F, Im YJ, Yoshimori T, Hurley JH . 6 . 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 . 32632011 . 7382272 . 10.1073/pnas.2008030117 . 2020PNAS..11717003B . free .
  4. Tabata K, Matsunaga K, Sakane A, Sasaki T, Noda T, Yoshimori T . 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 . 20943950 . 2993745 . 10.1091/mbc.E10-06-0495 .
  5. Nakamura S, Oba M, Suzuki M, Takahashi A, Yamamuro T, Fujiwara M, Ikenaka K, Minami S, Tabata N, Yamamoto K, Kubo S, Tokumura A, Akamatsu K, Miyazaki Y, Kawabata T, Hamasaki M, Fukui K, Sango K, Watanabe Y, Takabatake Y, Kitajima TS, Okada Y, Mochizuki H, Isaka Y, Antebi A, Yoshimori T . 6 . Suppression of autophagic activity by Rubicon is a signature of aging . Nature Communications . 10 . 1 . 847 . February 2019 . 30783089 . 6381146 . 10.1038/s41467-019-08729-6 .
  6. Heckmann BL, Teubner BJ, Tummers B, Boada-Romero E, Harris L, Yang M, Guy CS, Zakharenko SS, Green DR . 6 . LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease . Cell . 178 . 3 . 536–551.e14 . July 2019 . 31257024 . 6689199 . 10.1016/j.cell.2019.05.056 .
  7. Fang P, Yu H, Li M, He R, Zhu Y, Liu S . Rubicon: a facilitator of viral immune evasion . Cellular & Molecular Immunology . 16 . 9 . 770–771 . September 2019 . 31164715 . 6804746 . 10.1038/s41423-019-0248-7 .
  8. Yang CS, Rodgers M, Min CK, Lee JS, Kingeter L, Lee JY, Jong A, Kramnik I, Lin X, Jung JU . 6 . The autophagy regulator Rubicon is a feedback inhibitor of CARD9-mediated host innate immunity . Cell Host & Microbe . 11 . 3 . 277–289 . March 2012 . 22423967 . 3615900 . 10.1016/j.chom.2012.01.019 .
  9. Kim JH, Kim TH, Lee HC, Nikapitiya C, Uddin MB, Park ME, Pathinayake P, Lee ES, Chathuranga K, Herath TU, Chathuranga WA, Lee JS . 6 . Rubicon Modulates Antiviral Type I Interferon (IFN) Signaling by Targeting IFN Regulatory Factor 3 Dimerization . Journal of Virology . 91 . 14 . e00248–17 . July 2017 . 28468885 . 5487567 . 10.1128/JVI.00248-17 .
  10. Web site: RUBCN - Run domain Beclin-1-interacting and cysteine-rich domain-containing protein - Homo sapiens (Human) - RUBCN gene & protein . 2022-05-30 . www.uniprot.org . en.
  11. Web site: RCSB Protein Data Bank . RCSB PDB - 6WCW: Structure of human Rubicon RH domain in complex with GTP-bound Rab7 . 2022-06-30 . en-US.
  12. Sun Q, Zhang J, Fan W, Wong KN, Ding X, Chen S, Zhong Q . 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 . 21062745 . 3012973 . 10.1074/jbc.M110.126425 . free .
  13. Chang C, Young LN, Morris KL, von Bülow S, Schöneberg J, Yamamoto-Imoto H, Oe Y, Yamamoto K, Nakamura S, Stjepanovic G, Hummer G, Yoshimori T, Hurley JH . 6 . Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics . Molecular Cell . 73 . 2 . 339–353.e6 . January 2019 . 30581147 . 6450660 . 10.1016/j.molcel.2018.10.035 .
  14. Minami S, Nakamura S, Yoshimori T . Rubicon in Metabolic Diseases and Ageing . Frontiers in Cell and Developmental Biology . 9 . 816829 . 2021 . 35083223 . 8784836 . 10.3389/fcell.2021.816829 . free .
  15. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, Maejima I, Shirahama-Noda K, Ichimura T, Isobe T, Akira S, Noda T, Yoshimori T . 6 . Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages . Nature Cell Biology . 11 . 4 . 385–396 . April 2009 . 19270696 . 10.1038/ncb1846 . 205286778 .
  16. Tanaka S, Hikita H, Tatsumi T, Sakamori R, Nozaki Y, Sakane S, Shiode Y, Nakabori T, Saito Y, Hiramatsu N, Tabata K, Kawabata T, Hamasaki M, Eguchi H, Nagano H, Yoshimori T, Takehara T . 6 . Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice . Hepatology . 64 . 6 . 1994–2014 . December 2016 . 27637015 . 10.1002/hep.28820 . 205902404 .
  17. Yamamuro T, Kawabata T, Fukuhara A, Saita S, Nakamura S, Takeshita H, Fujiwara M, Enokidani Y, Yoshida G, Tabata K, Hamasaki M, Kuma A, Yamamoto K, Shimomura I, Yoshimori T . 6 . Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy . Nature Communications . 11 . 1 . 4150 . August 2020 . 32811819 . 7434891 . 10.1038/s41467-020-17985-w . 2020NatCo..11.4150Y .
  18. Web site: Spinocerebellar ataxia, autosomal recessive, 15 . 2022-05-30 . www.uniprot.org.
  19. Assoum M, Salih MA, Drouot N, H'Mida-Ben Brahim D, Lagier-Tourenne C, AlDrees A, Elmalik SA, Ahmed TS, Seidahmed MZ, Kabiraj MM, Koenig M . 6 . 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 . 20826435 . 10.1093/brain/awq181 . free .
  20. Assoum M, Salih MA, Drouot N, Hnia K, Martelli A, Koenig M . The Salih ataxia mutation impairs Rubicon endosomal localization . Cerebellum . 12 . 6 . 835–840 . December 2013 . 23728897 . 10.1007/s12311-013-0489-4 . 12372770 .

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