BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Ubiquitin-regulating effector proteins from Legionella

  • Jeong, Minwoo (Department of System Biology, College of Life Sciences and Biotechnology, Yonsei University) ;
  • Jeon, Hayoung (Department of System Biology, College of Life Sciences and Biotechnology, Yonsei University) ;
  • Shin, Donghyuk (Department of System Biology, College of Life Sciences and Biotechnology, Yonsei University)
  • Received : 2022.03.20
  • Accepted : 2022.05.30
  • Published : 2022.07.31
Download PDF
⟨ Previous Next ⟩

Abstract

Ubiquitin is relatively modest in size but involves almost entire cellular signaling pathways. The primary role of ubiquitin is maintaining cellular protein homeostasis. Ubiquitination regulates the fate of target proteins using the proteasome- or autophagy-mediated degradation of ubiquitinated substrates, which can be either intracellular or foreign proteins from invading pathogens. Legionella, a gram-negative intracellular pathogen, hinders the host-ubiquitin system by translocating hundreds of effector proteins into the host cell's cytoplasm. In this review, we describe the current understanding of ubiquitin machinery from Legionella. We summarize structural and biochemical differences between the host-ubiquitin system and ubiquitin-related effectors of Legionella. Some of these effectors act much like canonical host-ubiquitin machinery, whereas others have distinctive structures and accomplish non-canonical ubiquitination via novel biochemical mechanisms.

Keywords

Acknowledgement

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2021R1C1C100396112 and 2018R1A6A1A0302560722) and the Yonsei University Research Fund of 2021 (2021-22-0050).

References

  1. Hershko A and Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67, 425-479 https://doi.org/10.1146/annurev.biochem.67.1.425
  2. Mann M and Jensen ON (2003) Proteomic analysis of posttranslational modifications. Nat Biotechnol 21, 255-261 https://doi.org/10.1038/nbt0303-255
  3. Olsen JV and Mann M (2013) Status of large-scale analysis of post-translational modifications by mass spectrometry. Mol Cell Proteomics 12, 3444-3452 https://doi.org/10.1074/mcp.O113.034181
  4. Goldstein G, Scheid M, Hammerling U, Schlesinger DH, Niall HD and Boyse EA (1975) Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells. Proc Natl Acad Sci U S A 72, 11-15 https://doi.org/10.1073/pnas.72.1.11
  5. Yau R and Rape M (2016) The increasing complexity of the ubiquitin code. Nat Cell Biol 18, 579-586 https://doi.org/10.1038/ncb3358
  6. Gerlach B, Cordier SM, Schmukle AC et al (2011) Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591-596 https://doi.org/10.1038/nature09816
  7. Ikeda F, Rahighi S, Wakatsuki S and Dikic I (2011) Selective binding of linear ubiquitin chains to NEMO in NF-kappaB activation. Adv Exp Med Biol 691, 107-114 https://doi.org/10.1007/978-1-4419-6612-4_11
  8. Kirisako T, Kamei K, Murata S et al (2006) A ubiquitin ligase complex assembles linear polyubiquitin chains. EMBO J 25, 4877-4887 https://doi.org/10.1038/sj.emboj.7601360
  9. Tokunaga F, Sakata S, Saeki Y et al (2009) Involvement of linear polyubiquitylation of NEMO in NF-kappaB activation. Nat Cell Biol 11, 123-132 https://doi.org/10.1038/ncb1821
  10. Walczak H, Iwai K and Dikic I (2012) Generation and physiological roles of linear ubiquitin chains. BMC Biol 10, 23 https://doi.org/10.1186/1741-7007-10-23
  11. Morris JR and Solomon E (2004) BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair. Hum Mol Genet 13, 807-817 https://doi.org/10.1093/hmg/ddh095
  12. Nishikawa H, Ooka S, Sato K et al (2004) Mass spectrometric and mutational analyses reveal Lys-6-linked polyubiquitin chains catalyzed by BRCA1-BARD1 ubiquitin ligase. J Biol Chem 279, 3916-3924 https://doi.org/10.1074/jbc.M308540200
  13. Ordureau A, Sarraf SA, Duda DM et al (2014) Quantitative proteomics reveal a feedforward mechanism for mitochondrial PARKIN translocation and ubiquitin chain synthesis. Mol Cell 56, 360-375 https://doi.org/10.1016/j.molcel.2014.09.007
  14. Braten O, Livneh I, Ziv T et al (2016) Numerous proteins with unique characteristics are degraded by the 26S proteasome following monoubiquitination. Proc Natl Acad Sci U S A 113, E4639-E4647
  15. Chau V, Tobias JW, Bachmair A et al (1989) A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243, 1576-1583 https://doi.org/10.1126/science.2538923
  16. Gregori L, Poosch MS, Cousins G and Chau V (1990) A uniform isopeptide-linked multiubiquitin chain is sufficient to target substrate for degradation in ubiquitin-mediated proteolysis. J Biol Chem 265, 8354-8357 https://doi.org/10.1016/S0021-9258(19)38890-8
  17. Shabek N, Herman-Bachinsky Y, Buchsbaum S et al (2012) The size of the proteasomal substrate determines whether its degradation will be mediated by mono- or polyubiquitylation. Mol Cell 48, 87-97 https://doi.org/10.1016/j.molcel.2012.07.011
  18. Gatti M, Pinato S, Maiolica A et al (2015) RNF168 promotes noncanonical K27 ubiquitination to signal DNA damage. Cell Rep 10, 226-238 https://doi.org/10.1016/j.celrep.2014.12.021
  19. Clevers H and Nusse R (2012) Wnt/beta-catenin signaling and disease. Cell 149, 1192-1205 https://doi.org/10.1016/j.cell.2012.05.012
  20. Fei C, Li Z, Li C et al (2013) Smurf1-mediated Lys29-linked nonproteolytic polyubiquitination of axin negatively regulates Wnt/beta-catenin signaling. Mol Cell Biol 33, 4095-4105 https://doi.org/10.1128/MCB.00418-13
  21. Al-Hakim AK, Zagorska A, Chapman L, Deak M, Peggie M and Alessi DR (2008) Control of AMPK-related kinases by USP9X and atypical Lys(29)/Lys(33)-linked polyubiquitin chains. Biochem J 411, 249-260 https://doi.org/10.1042/BJ20080067
  22. Huang H, Jeon MS, Liao L et al (2010) K33-linked polyubiquitination of T cell receptor-zeta regulates proteolysis-independent T cell signaling. Immunity 33, 60-70 https://doi.org/10.1016/j.immuni.2010.07.002
  23. Thrower JS, Hoffman L, Rechsteiner M and Pickart CM (2000) Recognition of the polyubiquitin proteolytic signal. EMBO J 19, 94-102 https://doi.org/10.1093/emboj/19.1.94
  24. Duncan LM, Piper S, Dodd RB et al (2006) Lysine-63-linked ubiquitination is required for endolysosomal degradation of class I molecules. EMBO J 25, 1635-1645 https://doi.org/10.1038/sj.emboj.7601056
  25. Hofmann RM and Pickart CM (1999) Noncanonical MMS2-encoded ubiquitin-conjugating enzyme functions in assembly of novel polyubiquitin chains for DNA repair. Cell 96, 645-653 https://doi.org/10.1016/S0092-8674(00)80575-9
  26. Oeckinghaus A, Wegener E, Welteke V et al (2007) Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation. EMBO J 26, 4634-4645 https://doi.org/10.1038/sj.emboj.7601897
  27. Ni X, Kou W, Gu J et al (2019) TRAF6 directs FOXP3 localization and facilitates regulatory T-cell function through K63-linked ubiquitination. EMBO J 38, e99766 https://doi.org/10.15252/embj.201899766
  28. Wang J, Yang S, Liu L, Wang H and Yang B (2017) HTLV-1 Tax impairs K63-linked ubiquitination of STING to evade host innate immunity. Virus Res 232, 13-21 https://doi.org/10.1016/j.virusres.2017.01.016
  29. Husnjak K and Dikic I (2012) Ubiquitin-binding proteins: decoders of ubiquitin-mediated cellular functions. Annu Rev Biochem 81, 291-322 https://doi.org/10.1146/annurev-biochem-051810-094654
  30. Schulman BA and Harper JW (2009) Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol 10, 319-331 https://doi.org/10.1038/nrm2673
  31. Olsen SK and Lima CD (2013) Structure of a ubiquitin E1-E2 complex: insights to E1-E2 thioester transfer. Mol Cell 49, 884-896 https://doi.org/10.1016/j.molcel.2013.01.013
  32. Ye Y and Rape M (2009) Building ubiquitin chains: E2 enzymes at work. Nat Rev Mol Cell Biol 10, 755-764 https://doi.org/10.1038/nrm2780
  33. Buetow L and Huang DT (2016) Structural insights into the catalysis and regulation of E3 ubiquitin ligases. Nat Rev Mol Cell Biol 17, 626-642 https://doi.org/10.1038/nrm.2016.91
  34. Deshaies RJ and Joazeiro CA (2009) RING domain E3 ubiquitin ligases. Annu Rev Biochem 78, 399-434 https://doi.org/10.1146/annurev.biochem.78.101807.093809
  35. Berndsen CE and Wolberger C (2014) New insights into ubiquitin E3 ligase mechanism. Nat Struct Mol Biol 21, 301-307 https://doi.org/10.1038/nsmb.2780
  36. Lorick KL, Jensen JP, Fang S, Ong AM, Hatakeyama S and Weissman AM (1999) RING fingers mediate ubiquitin-conjugating enzyme (E2)-dependent ubiquitination. Proc Natl Acad Sci U S A 96, 11364-11369 https://doi.org/10.1073/pnas.96.20.11364
  37. Ohi MD, Vander Kooi CW, Rosenberg JA, Chazin WJ and Gould KL (2003) Structural insights into the U-box, a domain associated with multi-ubiquitination. Nat Struct Biol 10, 250-255 https://doi.org/10.1038/nsb906
  38. Marin I and Ferrus A (2002) Comparative genomics of the RBR family, including the Parkinson's disease-related gene parkin and the genes of the ariadne subfamily. Mol Biol Evol 19, 2039-2050 https://doi.org/10.1093/oxfordjournals.molbev.a004029
  39. Spratt DE, Walden H and Shaw GS (2014) RBR E3 ubiquitin ligases: new structures, new insights, new questions. Biochem J 458, 421-437 https://doi.org/10.1042/BJ20140006
  40. Kwasna D, Abdul Rehman SA, Natarajan J et al (2018) Discovery and characterization of ZUFSP/ZUP1, a distinct deubiquitinase class important for genome stability. Mol Cell 70, 150-164 e156 https://doi.org/10.1016/j.molcel.2018.02.023
  41. Reyes-Turcu FE, Ventii KH and Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 78, 363-397 https://doi.org/10.1146/annurev.biochem.78.082307.091526
  42. Fields BS, Benson RF and Besser RE (2002) Legionella and Legionnaires' disease: 25 years of investigation. Clin Microbiol Rev 15, 506-526 https://doi.org/10.1128/CMR.15.3.506-526.2002
  43. Ashida H, Kim M and Sasakawa C (2014) Exploitation of the host ubiquitin system by human bacterial pathogens. Nat Rev Microbiol 12, 399-413 https://doi.org/10.1038/nrmicro3259
  44. Choy A, Dancourt J, Mugo B et al (2012) The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338, 1072-1076 https://doi.org/10.1126/science.1227026
  45. Liu Y, Mukherjee R, Bonn F et al (2021) Serine-ubiquitination regulates Golgi morphology and the secretory pathway upon Legionella infection. Cell Death Differ 28, 2957-2969 https://doi.org/10.1038/s41418-021-00830-y
  46. Shin D, Mukherjee R, Liu Y et al (2020) Regulation of phosphoribosyl-linked serine ubiquitination by deubiquitinases DupA and DupB. Mol Cell 77, 164-179 e166 https://doi.org/10.1016/j.molcel.2019.10.019
  47. Wan M, Wang X, Huang C et al (2019) A bacterial effector deubiquitinase specifically hydrolyses linear ubiquitin chains to inhibit host inflammatory signalling. Nat Microbiol 4, 1282-1293 https://doi.org/10.1038/s41564-019-0454-1
  48. Ensminger AW and Isberg RR (2010) E3 ubiquitin ligase activity and targeting of BAT3 by multiple Legionella pneumophila translocated substrates. Infect Immun 78, 3905-3919 https://doi.org/10.1128/IAI.00344-10
  49. Price CT, Al-Khodor S, Al-Quadan T et al (2009) Molecular mimicry by an F-box effector of Legionella pneumophila hijacks a conserved polyubiquitination machinery within macrophages and protozoa. PLoS Pathog 5, e1000704 https://doi.org/10.1371/journal.ppat.1000704
  50. Miyamoto K and Saito K (2018) Concise machinery for monitoring ubiquitination activities using novel artificial RING fingers. Protein Sci 27, 1354-1363 https://doi.org/10.1002/pro.3427
  51. Kubori T, Hyakutake A and Nagai H (2008) Legionella translocates an E3 ubiquitin ligase that has multiple U-boxes with distinct functions. Mol Microbiol 67, 1307-1319 https://doi.org/10.1111/j.1365-2958.2008.06124.x
  52. Kubori T, Shinzawa N, Kanuka H and Nagai H (2010) Legionella metaeffector exploits host proteasome to temporally regulate cognate effector. PLoS Pathog 6, e1001216 https://doi.org/10.1371/journal.ppat.1001216
  53. Quaile AT, Urbanus ML, Stogios PJ et al (2015) Molecular characterization of LubX: functional divergence of the u-box fold by Legionella pneumophila. Structure 23, 1459-1469 https://doi.org/10.1016/j.str.2015.05.020
  54. Benirschke RC, Thompson JR, Nomine Y et al (2010) Molecular basis for the association of human E4B U box ubiquitin ligase with E2-conjugating enzymes UbcH5c and Ubc4. Structure 18, 955-965 https://doi.org/10.1016/j.str.2010.04.017
  55. Mevissen TET and Komander D (2017) Mechanisms of deubiquitinase specificity and regulation. Annu Rev Biochem 86, 159-192 https://doi.org/10.1146/annurev-biochem-061516-044916
  56. Edelmann MJ, Iphofer A, Akutsu M et al (2009) Structural basis and specificity of human otubain 1-mediated deubiquitination. Biochem J 418, 379-390 https://doi.org/10.1042/BJ20081318
  57. Keusekotten K, Elliott PR, Glockner L et al (2013) OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell 153, 1312-1326 https://doi.org/10.1016/j.cell.2013.05.014
  58. Mevissen TE, Hospenthal MK, Geurink PP et al (2013) OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell 154, 169-184 https://doi.org/10.1016/j.cell.2013.05.046
  59. Kitao T, Nagai H and Kubori T (2020) Divergence of Legionella effectors reversing conventional and unconventional ubiquitination. Front Cell Infect Microbiol 10, 448 https://doi.org/10.3389/fcimb.2020.00448
  60. Shin D, Bhattacharya A, Cheng YL et al (2020) Bacterial OTU deubiquitinases regulate substrate ubiquitination upon Legionella infection. Elife 9, e58277 https://doi.org/10.7554/eLife.58277
  61. Takekawa N, Kubori T, Iwai T, Nagai H and Imada K (2022) Structural basis of ubiquitin recognition by a bacterial ovarian tumor deubiquitinase LotA. J Bacteriol 204, e0037621 https://doi.org/10.1128/JB.00376-21
  62. Kitao T, Taguchi K, Seto S et al (2020) Legionella manipulates non-canonical SNARE pairing using a bacterial deubiquitinase. Cell Rep 32, 108107 https://doi.org/10.1016/j.celrep.2020.108107
  63. Ma K, Zhen X, Zhou B et al (2020) The bacterial deubiquitinase Ceg23 regulates the association of Lys-63-linked polyubiquitin molecules on the Legionella phagosome. J Biol Chem 295, 1646-1657 https://doi.org/10.1074/jbc.ra119.011758
  64. Schubert AF, Nguyen JV, Franklin TG et al (2020) Identification and characterization of diverse OTU deubiquitinases in bacteria. EMBO J 39, e105127 https://doi.org/10.15252/embj.2020105127
  65. Schulze-Niemand E, Naumann M and Stein M (2021) The activation and selectivity of the Legionella RavD deubiquitinase. Front Mol Biosci 8, 770320 https://doi.org/10.3389/fmolb.2021.770320
  66. Schulze-Niemand E, Naumann M and Stein M (2022) Substrate-assisted activation and selectivity of the bacterial RavD effector deubiquitinylase. Proteins 90, 947-958 https://doi.org/10.1002/prot.26286
  67. Qiu J, Sheedlo MJ, Yu K et al (2016) Ubiquitination independent of E1 and E2 enzymes by bacterial effectors. Nature 533, 120-124 https://doi.org/10.1038/nature17657
  68. Bhogaraju S, Kalayil S, Liu Y et al (2016) Phosphoribosylation of ubiquitin promotes serine ubiquitination and impairs conventional ubiquitination. Cell 167, 1636-1649 e1613 https://doi.org/10.1016/j.cell.2016.11.019
  69. Wan M, Sulpizio AG, Akturk A et al (2019) Deubiquitination of phosphoribosyl-ubiquitin conjugates by phosphodiesterase-domain-containing Legionella effectors. Proc Natl Acad Sci U S A 116, 23518-23526 https://doi.org/10.1073/pnas.1916287116
  70. Black MH, Osinski A, Gradowski M et al (2019) Bacterial pseudokinase catalyzes protein polyglutamylation to inhibit the SidE-family ubiquitin ligases. Science 364, 787-792 https://doi.org/10.1126/science.aaw7446
  71. Bhogaraju S, Bonn F, Mukherjee R et al (2019) Inhibition of bacterial ubiquitin ligases by SidJ-calmodulin catalysed glutamylation. Nature 572, 382-386 https://doi.org/10.1038/s41586-019-1440-8
  72. Song L, Xie Y, Li C et al (2021) The Legionella effector SdjA is a bifunctional enzyme that distinctly regulates phosphoribosyl ubiquitination. mBio 12, e0231621 https://doi.org/10.1128/mBio.02316-21
  73. Gan N, Zhen X, Liu Y et al (2019) Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase. Nature 572, 387-391 https://doi.org/10.1038/s41586-019-1439-1
  74. Osinski A, Black MH, Pawlowski K, Chen Z, Li Y and Tagliabracci VS (2021) Structural and mechanistic basis for protein glutamylation by the kinase fold. Mol Cell 81, 4527-4539 e4528 https://doi.org/10.1016/j.molcel.2021.08.007
  75. Adams M, Sharma R, Colby T, Weis F, Matic I and Bhogaraju S (2021) Structural basis for protein glutamylation by the Legionella pseudokinase SidJ. Nat Commun 12, 6174 https://doi.org/10.1038/s41467-021-26429-y
  76. Akturk A, Wasilko DJ, Wu X et al (2018) Mechanism of phosphoribosyl-ubiquitination mediated by a single Legionella effector. Nature 557, 729-733 https://doi.org/10.1038/s41586-018-0147-6
  77. Dong Y, Mu Y, Xie Y et al (2018) Structural basis of ubiquitin modification by the Legionella effector SdeA. Nature 557, 674-678 https://doi.org/10.1038/s41586-018-0146-7
  78. Kalayil S, Bhogaraju S, Bonn F et al (2018) Insights into catalysis and function of phosphoribosyl-linked serine ubiquitination. Nature 557, 734-738 https://doi.org/10.1038/s41586-018-0145-8
  79. Wang Y, Shi M, Feng H et al (2018) Structural insights into non-canonical ubiquitination catalyzed by SidE. Cell 173, 1231-1243 e1216 https://doi.org/10.1016/j.cell.2018.04.023
  80. Prokhorova E, Zobel F, Smith R et al (2021) Serine-linked PARP1 auto-modification controls PARP inhibitor response. Nat Commun 12, 4055 https://doi.org/10.1038/s41467-021-24361-9
  81. Valleau D, Quaile AT, Cui H et al (2018) Discovery of ubiquitin deamidases in the pathogenic arsenal of Legionella pneumophila. Cell Rep 23, 568-583 https://doi.org/10.1016/j.celrep.2018.03.060
  82. Puvar K, Iyer S, Fu J et al (2020) Legionella effector MavC targets the Ube2N-Ub conjugate for noncanonical ubiquitination. Nat Commun 11, 2365 https://doi.org/10.1038/s41467-020-16211-x
  83. Guan H, Fu J, Yu T et al (2020) Molecular basis of ubiquitination catalyzed by the bacterial transglutaminase MavC. Adv Sci (Weinh) 7, 2000871 https://doi.org/10.1002/advs.202000871
  84. Gan N, Guan H, Huang Y et al (2020) Legionella pneumophila regulates the activity of UBE2N by deamidase-mediated deubiquitination. EMBO J 39, e102806 https://doi.org/10.15252/embj.2019102806
  85. Mu Y, Wang Y, Huang Y et al (2020) Structural insights into the mechanism and inhibition of transglutaminase-induced ubiquitination by the Legionella effector MavC. Nat Commun 11, 1774 https://doi.org/10.1038/s41467-020-15645-7