5haf › Citations

The Molecular Basis for Ubiquitin and Ubiquitin-like Specificities in Bacterial Effector Proteases.

<div class='caption-title'>CE Effector Proteins Demonstrate Mixed Activities</div>
<div class='caption-title'>Structural Analysis of Bacterial CE Deubiquitinases</div>
<div class='caption-title'>Molecular Analysis of XopD Ub/Ubl Specificity</div>
Pruneda JN, Durkin CH, Geurink PP, Ovaa H, Santhanam B, Holden DW, Komander D
OpenAccess logo Mol Cell 63 261-276 (2016)
Related entries: 5hag, 5ham, 5jp1, 5jp3

Cited: 78 times
EuropePMC logo PMID: 27425412

Abstract

Pathogenic bacteria rely on secreted effector proteins to manipulate host signaling pathways, often in creative ways. CE clan proteases, specific hydrolases for ubiquitin-like modifications (SUMO and NEDD8) in eukaryotes, reportedly serve as bacterial effector proteins with deSUMOylase, deubiquitinase, or, even, acetyltransferase activities. Here, we characterize bacterial CE protease activities, revealing K63-linkage-specific deubiquitinases in human pathogens, such as Salmonella, Escherichia, and Shigella, as well as ubiquitin/ubiquitin-like cross-reactive enzymes in Chlamydia, Rickettsia, and Xanthomonas. Five crystal structures, including ubiquitin/ubiquitin-like complexes, explain substrate specificities and redefine relationships across the CE clan. Importantly, this work identifies novel family members and provides key discoveries among previously reported effectors, such as the unexpected deubiquitinase activity in Xanthomonas XopD, contributed by an unstructured ubiquitin binding region. Furthermore, accessory domains regulate properties such as subcellular localization, as exemplified by a ubiquitin-binding domain in Salmonella Typhimurium SseL. Our work both highlights and explains the functional adaptations observed among diverse CE clan proteins.

Reviews - 5haf mentioned but not cited (1)

  1. Speaking the host language: how Salmonella effector proteins manipulate the host. Pillay TD, Hettiarachchi SU, Gan J, Diaz-Del-Olmo I, Yu XJ, Muench JH, Thurston TLM, Pearson JS. Microbiology (Reading) 169 (2023)

Articles - 5haf mentioned but not cited (1)

  1. A deubiquitylase with an unusually high-affinity ubiquitin-binding domain from the scrub typhus pathogen Orientia tsutsugamushi. Berk JM, Lim C, Ronau JA, Chaudhuri A, Chen H, Beckmann JF, Loria JP, Xiong Y, Hochstrasser M. Nat Commun 11 2343 (2020)


Reviews citing this publication (29)

  1. Mechanisms of Deubiquitinase Specificity and Regulation. Mevissen TET, Komander D. Annu Rev Biochem 86 159-192 (2017)
  2. Deubiquitylating enzymes and drug discovery: emerging opportunities. Harrigan JA, Jacq X, Martin NM, Jackson SP. Nat Rev Drug Discov 17 57-78 (2018)
  3. Principles of Ubiquitin-Dependent Signaling. Oh E, Akopian D, Rape M. Annu Rev Cell Dev Biol 34 137-162 (2018)
  4. Selective Autophagy and Xenophagy in Infection and Disease. Sharma V, Verma S, Seranova E, Sarkar S, Kumar D. Front Cell Dev Biol 6 147 (2018)
  5. Activity-based probes for the ubiquitin conjugation-deconjugation machinery: new chemistries, new tools, and new insights. Hewings DS, Flygare JA, Bogyo M, Wertz IE. FEBS J 284 1555-1576 (2017)
  6. Resolving the Complexity of Ubiquitin Networks. Kliza K, Husnjak K. Front Mol Biosci 7 21 (2020)
  7. Exploitation of the host cell ubiquitin machinery by microbial effector proteins. Lin YH, Machner MP. J Cell Sci 130 1985-1996 (2017)
  8. Structure and Function of Viral Deubiquitinating Enzymes. Bailey-Elkin BA, Knaap RCM, Kikkert M, Mark BL. J Mol Biol 429 3441-3470 (2017)
  9. Ubiquitin, SUMO, and NEDD8: Key Targets of Bacterial Pathogens. Ribet D, Cossart P. Trends Cell Biol 28 926-940 (2018)
  10. Fifty shades of SUMO: its role in immunity and at the fulcrum of the growth-defence balance. Verma V, Croley F, Sadanandom A. Mol Plant Pathol 19 1537-1544 (2018)
  11. Divergence of Legionella Effectors Reversing Conventional and Unconventional Ubiquitination. Kitao T, Nagai H, Kubori T. Front Cell Infect Microbiol 10 448 (2020)
  12. The Biochemistry of Cytoplasmic Incompatibility Caused by Endosymbiotic Bacteria. Chen H, Zhang M, Hochstrasser M. Genes (Basel) 11 E852 (2020)
  13. Immunomodulatory Yersinia outer proteins (Yops)-useful tools for bacteria and humans alike. Grabowski B, Schmidt MA, Rüter C. Virulence 8 1124-1147 (2017)
  14. Bacterial secretion systems and regulation of inflammasome activation. Ratner D, Orning MP, Lien E. J Leukoc Biol 101 165-181 (2017)
  15. Uncovering the Structural Basis of a New Twist in Protein Ubiquitination. Puvar K, Luo ZQ, Das C. Trends Biochem Sci 44 467-477 (2019)
  16. The Ubiquitination System within Bacterial Host-Pathogen Interactions. Vozandychova V, Stojkova P, Hercik K, Rehulka P, Stulik J. Microorganisms 9 638 (2021)
  17. Bacteria make surgical strikes on host ubiquitin signaling. Franklin TG, Pruneda JN. PLoS Pathog 17 e1009341 (2021)
  18. Modification of the host ubiquitome by bacterial enzymes. Berglund J, Gjondrekaj R, Verney E, Maupin-Furlow JA, Edelmann MJ. Microbiol Res 235 126429 (2020)
  19. The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome. Li T, Zou C. Int J Mol Sci 21 E4842 (2020)
  20. Ubiquitin-targeted bacterial effectors: rule breakers of the ubiquitin system. Roberts CG, Franklin TG, Pruneda JN. EMBO J 42 e114318 (2023)
  21. Understanding and Exploiting Post-Translational Modifications for Plant Disease Resistance. Gough C, Sadanandom A. Biomolecules 11 1122 (2021)
  22. Insights Into Mitochondrial Dynamics in Chlamydial Infection. Yang Y, Lei W, Zhao L, Wen Y, Li Z. Front Cell Infect Microbiol 12 835181 (2022)
  23. Post-translational Lysine Ac(et)ylation in Bacteria: A Biochemical, Structural, and Synthetic Biological Perspective. Lammers M. Front Microbiol 12 757179 (2021)
  24. Bacterial usurpation of the OTU deubiquitinase fold. Pruneda JN, Nguyen JV, Nagai H, Kubori T. FEBS J (2023)
  25. Targeting the Ubiquitin-Proteasome System and Recent Advances in Cancer Therapy. Spano D, Catara G. Cells 13 29 (2023)
  26. Diverse ubiquitin codes in the regulation of inflammatory signaling. Ikeda F. Proc Jpn Acad Ser B Phys Biol Sci 96 431-439 (2020)
  27. How to Target Viral and Bacterial Effector Proteins Interfering with Ubiquitin Signaling. van der Heden van Noort GJ, Ovaa H. Curr Top Microbiol Immunol 420 111-130 (2019)
  28. In the moonlight: non-catalytic functions of ubiquitin and ubiquitin-like proteases. Campos Alonso M, Knobeloch KP. Front Mol Biosci 11 1349509 (2024)
  29. The emerging role and therapeutic implications of bacterial and parasitic deubiquitinating enzymes. Wehrmann M, Vilchez D. Front Immunol 14 1303072 (2023)

Articles citing this publication (47)

  1. SseK1 and SseK3 Type III Secretion System Effectors Inhibit NF-κB Signaling and Necroptotic Cell Death in Salmonella-Infected Macrophages. Günster RA, Matthews SA, Holden DW, Thurston TLM. Infect Immun 85 e00010-17 (2017)
  2. Chlamydia trachomatis-containing vacuole serves as deubiquitination platform to stabilize Mcl-1 and to interfere with host defense. Fischer A, Harrison KS, Ramirez Y, Auer D, Chowdhury SR, Prusty BK, Sauer F, Dimond Z, Kisker C, Hefty PS, Rudel T. Elife 6 e21465 (2017)
  3. Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies. Swatek KN, Aumayr M, Pruneda JN, Visser LJ, Berryman S, Kueck AF, Geurink PP, Ovaa H, van Kuppeveld FJM, Tuthill TJ, Skern T, Komander D. Proc Natl Acad Sci U S A 115 2371-2376 (2018)
  4. Evasion of autophagy mediated by Rickettsia surface protein OmpB is critical for virulence. Engström P, Burke TP, Mitchell G, Ingabire N, Mark KG, Golovkine G, Iavarone AT, Rape M, Cox JS, Welch MD. Nat Microbiol 4 2538-2551 (2019)
  5. A Chlamydia effector combining deubiquitination and acetylation activities induces Golgi fragmentation. Pruneda JN, Bastidas RJ, Bertsoulaki E, Swatek KN, Santhanam B, Clague MJ, Valdivia RH, Urbé S, Komander D. Nat Microbiol 3 1377-1384 (2018)
  6. LotA, a Legionella deubiquitinase, has dual catalytic activity and contributes to intracellular growth. Kubori T, Kitao T, Ando H, Nagai H. Cell Microbiol 20 e12840 (2018)
  7. Sumoylation in plants: mechanistic insights and its role in drought stress. Benlloch R, Lois LM. J Exp Bot 69 4539-4554 (2018)
  8. Identification and characterization of diverse OTU deubiquitinases in bacteria. Schubert AF, Nguyen JV, Franklin TG, Geurink PP, Roberts CG, Sanderson DJ, Miller LN, Ovaa H, Hofmann K, Pruneda JN, Komander D. EMBO J 39 e105127 (2020)
  9. Mechanism of host substrate acetylation by a YopJ family effector. Zhang ZM, Ma KW, Gao L, Hu Z, Schwizer S, Ma W, Song J. Nat Plants 3 17115 (2017)
  10. Distinct USP25 and USP28 Oligomerization States Regulate Deubiquitinating Activity. Gersch M, Wagstaff JL, Toms AV, Graves B, Freund SMV, Komander D. Mol Cell 74 436-451.e7 (2019)
  11. A Tangled Web: Origins of Reproductive Parasitism. Gillespie JJ, Driscoll TP, Verhoeve VI, Rahman MS, Macaluso KR, Azad AF. Genome Biol Evol 10 2292-2309 (2018)
  12. Crystal Structure of African Swine Fever Virus pS273R Protease and Implications for Inhibitor Design. Li G, Liu X, Yang M, Zhang G, Wang Z, Guo K, Gao Y, Jiao P, Sun J, Chen C, Wang H, Deng W, Xiao H, Li S, Wu H, Wang Y, Cao L, Jia Z, Shang L, Yang C, Guo Y, Rao Z. J Virol 94 e02125-19 (2020)
  13. The Salmonella Effector SpvD Is a Cysteine Hydrolase with a Serovar-specific Polymorphism Influencing Catalytic Activity, Suppression of Immune Responses, and Bacterial Virulence. Grabe GJ, Zhang Y, Przydacz M, Rolhion N, Yang Y, Pruneda JN, Komander D, Holden DW, Hare SA. J Biol Chem 291 25853-25863 (2016)
  14. Evolution of Wolbachia mutualism and reproductive parasitism: insight from two novel strains that co-infect cat fleas. Driscoll TP, Verhoeve VI, Brockway C, Shrewsberry DL, Plumer M, Sevdalis SE, Beckmann JF, Krueger LM, Macaluso KR, Azad AF, Gillespie JJ. PeerJ 8 e10646 (2020)
  15. Interaction of the Ankyrin H Core Effector of Legionella with the Host LARP7 Component of the 7SK snRNP Complex. Von Dwingelo J, Chung IYW, Price CT, Li L, Jones S, Cygler M, Abu Kwaik Y. mBio 10 e01942-19 (2019)
  16. Structural insights into the architecture and membrane interactions of the conserved COMMD proteins. Healy MD, Hospenthal MK, Hall RJ, Chandra M, Chilton M, Tillu V, Chen KE, Celligoi DJ, McDonald FJ, Cullen PJ, Lott JS, Collins BM, Ghai R. Elife 7 e35898 (2018)
  17. Bacterial OTU deubiquitinases regulate substrate ubiquitination upon Legionella infection. Shin D, Bhattacharya A, Cheng YL, Alonso MC, Mehdipour AR, van der Heden van Noort GJ, Ovaa H, Hummer G, Dikic I. Elife 9 e58277 (2020)
  18. A High-Throughput Assay for Monitoring Ubiquitination in Real Time. Franklin TG, Pruneda JN. Front Chem 7 816 (2019)
  19. An evolutionary approach to systematic discovery of novel deubiquitinases, applied to Legionella. Hermanns T, Woiwode I, Guerreiro RF, Vogt R, Lammers M, Hofmann K. Life Sci Alliance 3 e202000838 (2020)
  20. Legionella effector MavC targets the Ube2N~Ub conjugate for noncanonical ubiquitination. Puvar K, Iyer S, Fu J, Kenny S, Negrón Terón KI, Luo ZQ, Brzovic PS, Klevit RE, Das C. Nat Commun 11 2365 (2020)
  21. Evaluating enzyme activities and structures of DUBs. Pruneda JN, Komander D. Methods Enzymol 618 321-341 (2019)
  22. NopD of Bradyrhizobium sp. XS1150 Possesses SUMO Protease Activity. Xiang QW, Bai J, Cai J, Huang QY, Wang Y, Liang Y, Zhong Z, Wagner C, Xie ZP, Staehelin C. Front Microbiol 11 386 (2020)
  23. Mechanism of Lys6 poly-ubiquitin specificity by the L. pneumophila deubiquitinase LotA. Warren GD, Kitao T, Franklin TG, Nguyen JV, Geurink PP, Kubori T, Nagai H, Pruneda JN. Mol Cell 83 105-120.e5 (2023)
  24. Expressed Protein Ligation without Intein. Qiao Y, Yu G, Kratch KC, Wang XA, Wang WW, Leeuwon SZ, Xu S, Morse JS, Liu WR. J Am Chem Soc 142 7047-7054 (2020)
  25. Identification of UBact, a ubiquitin-like protein, along with other homologous components of a conjugation system and the proteasome in different gram-negative bacteria. Lehmann G, Udasin RG, Livneh I, Ciechanover A. Biochem Biophys Res Commun 483 946-950 (2017)
  26. Profiling DUBs and Ubl-specific proteases with activity-based probes. Geurink PP, van der Heden van Noort GJ, Mulder MPC, Knaap RCM, Kikkert M, Ovaa H. Methods Enzymol 618 357-387 (2019)
  27. A widely distributed family of eukaryotic and bacterial deubiquitinases related to herpesviral large tegument proteins. Erven I, Abraham E, Hermanns T, Baumann U, Hofmann K. Nat Commun 13 7643 (2022)
  28. Crystal Structures of Wolbachia CidA and CidB Reveal Determinants of Bacteria-induced Cytoplasmic Incompatibility and Rescue. Wang H, Xiao Y, Chen X, Zhang M, Sun G, Wang F, Wang L, Zhang H, Zhang X, Yang X, Li W, Wei Y, Yao D, Zhang B, Li J, Cui W, Wang F, Chen C, Shen W, Su D, Bai F, Huang J, Ye S, Zhang L, Ji X, Wang W, Wang Z, Hochstrasser M, Yang H. Nat Commun 13 1608 (2022)
  29. FoxJ1 inhibits African swine fever virus replication and viral S273R protein decreases the expression of FoxJ1 to impair its antiviral effect. Ma C, Li S, Yang F, Cao W, Liu H, Feng T, Zhang K, Zhu Z, Liu X, Hu Y, Zheng H. Virol Sin 37 445-454 (2022)
  30. The Two Deubiquitinating Enzymes from Chlamydia trachomatis Have Distinct Ubiquitin Recognition Properties. Hausman JM, Kenny S, Iyer S, Babar A, Qiu J, Fu J, Luo ZQ, Das C. Biochemistry 59 1604-1617 (2020)
  31. Structural Basis of Substrate Recognition and Covalent Inhibition of Cdu1 from Chlamydia trachomatis. Ramirez YA, Adler TB, Altmann E, Klemm T, Tiesmeyer C, Sauer F, Kathman SG, Statsyuk AV, Sotriffer C, Kisker C. ChemMedChem 13 2014-2023 (2018)
  32. Native Semisynthesis of Isopeptide-Linked Substrates for Specificity Analysis of Deubiquitinases and Ubl Proteases. Zhao Z, O'Dea R, Wendrich K, Kazi N, Gersch M. J Am Chem Soc 145 20801-20812 (2023)
  33. Secondary-structure switch regulates the substrate binding of a YopJ family acetyltransferase. Xia Y, Zou R, Escouboué M, Zhong L, Zhu C, Pouzet C, Wu X, Wang Y, Lv G, Zhou H, Sun P, Sun P, Ding K, Deslandes L, Yuan S, Zhang ZM. Nat Commun 12 5969 (2021)
  34. Insights into Ubiquitin Product Release in Hydrolysis Catalyzed by the Bacterial Deubiquitinase SdeA. Sheedlo MJ, Kenny S, Podkorytov IS, Brown K, Ma J, Iyer S, Hewitt CS, Arbough T, Mikhailovskii O, Flaherty DP, Wilson MA, Skrynnikov NR, Das C. Biochemistry 60 584-596 (2021)
  35. Molecular basis for ubiquitin/Fubi cross-reactivity in USP16 and USP36. O'Dea R, Kazi N, Hoffmann-Benito A, Zhao Z, Recknagel S, Wendrich K, Janning P, Gersch M. Nat Chem Biol 19 1394-1405 (2023)
  36. OtDUB from the Human Pathogen Orientia tsutsugamushi Modulates Host Membrane Trafficking by Multiple Mechanisms. Berk JM, Lee MJ, Zhang M, Lim C, Hochstrasser M. Mol Cell Biol 42 e0007122 (2022)
  37. Structural insights into ubiquitin chain cleavage by Legionella ovarian tumor deubiquitinases. Kang S, Kim G, Choi M, Jeong M, van der Heden van Noort GJ, Roh SH, Shin D. Life Sci Alliance 6 e202201876 (2023)
  38. Identification and classification of papain-like cysteine proteinases. Ozhelvaci F, Steczkiewicz K. J Biol Chem 299 104801 (2023)
  39. Insights Into Drug Repurposing, as Well as Specificity and Compound Properties of Piperidine-Based SARS-CoV-2 PLpro Inhibitors. Calleja DJ, Kuchel N, Lu BGC, Birkinshaw RW, Klemm T, Doerflinger M, Cooney JP, Mackiewicz L, Au AE, Yap YQ, Blackmore TR, Katneni K, Crighton E, Newman J, Jarman KE, Call MJ, Lechtenberg BC, Czabotar PE, Pellegrini M, Charman SA, Lowes KN, Mitchell JP, Nachbur U, Lessene G, Komander D. Front Chem 10 861209 (2022)
  40. Structural and functional study of Legionella pneumophila effector RavA. Chung IYW, Li L, Tyurin O, Gagarinova A, Wibawa R, Li P, Hartland EL, Cygler M. Protein Sci 30 940-955 (2021)
  41. The Coxiella burnetii effector EmcB is a deubiquitinase that inhibits RIG-I signaling. Duncan-Lowey J, Crabill E, Jarret A, Reed SCO, Roy CR. Proc Natl Acad Sci U S A 120 e2217602120 (2023)
  42. Bioinformatical Approaches to the Discovery and Classification of Novel Deubiquitinases. Hermanns T, Hofmann K. Methods Mol Biol 2591 135-149 (2023)
  43. Functional and structural diversity in deubiquitinases of the Chlamydia-like bacterium Simkania negevensis. Boll V, Hermanns T, Uthoff M, Erven I, Hörner EM, Kozjak-Pavlovic V, Baumann U, Hofmann K. Nat Commun 14 7335 (2023)
  44. The PH Domain and C-Terminal polyD Motif of Phafin2 Exhibit a Unique Concurrence in Animals. Hasan M, Capelluto DGS. Membranes (Basel) 12 696 (2022)
  45. The acetylase activity of Cdu1 regulates bacterial exit from infected cells by protecting Chlamydia effectors from degradation. Bastidas RJ, Kędzior M, Davidson RK, Walsh SC, Dolat L, Sixt BS, Pruneda JN, Coers J, Valdivia RH. Elife 12 RP87386 (2024)
  46. Cocrystallization of ubiquitin-deubiquitinase complexes through disulfide linkage. Negron Teron KI, Das C. Acta Crystallogr D Struct Biol 79 1044-1055 (2023)
  47. The structural basis for deubiquitination by the fingerless USP-type effector TssM. Hermanns T, Uthoff M, Baumann U, Hofmann K. Life Sci Alliance 7 e202302422 (2024)


Quick links