Bacterial ubiquitin ligases hijack the host deubiquitinase OTUB1 to inhibit MTORC1 signaling and promote autophagy

References

• Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67(1):425–479. doi: 10.1146/annurev.biochem.67.1.425
   PubMedGoogle Scholar
• Pickart CM. Mechanisms underlying ubiquitination. Annu Rev Biochem. 2001;70(1):503–533. doi: 10.1146/annurev.biochem.70.1.503
   PubMed Web of Science ®Google Scholar
• Morreale FE, Walden H. Types of ubiquitin ligases. Cell. 2016;165(1):248–248 e1. doi: 10.1016/j.cell.2016.03.003
   PubMed Web of Science ®Google Scholar
• Mevissen TET, Komander D. Mechanisms of deubiquitinase specificity and Regulation. Annu Rev Biochem. 2017;86(1):159–192. doi: 10.1146/annurev-biochem-061516-044916
   PubMedGoogle Scholar
• Yau R, Rape M. The increasing complexity of the ubiquitin code. Nat Cell Biol. 2016;18(6):579–586. doi: 10.1038/ncb3358
   PubMed Web of Science ®Google Scholar
• Mukherjee R, Dikic I. Regulation of Host-Pathogen interactions via the Ubiquitin System. Annu Rev Microbiol. 2022;76(1):211–233. doi: 10.1146/annurev-micro-041020-025803
   PubMedGoogle Scholar
• Ullrich S, Nitsche C. SARS-CoV-2 papain-like protease: structure, function and inhibition. Chembiochem. 2022;23(19):e202200327. doi: 10.1002/cbic.202200327
   PubMed Web of Science ®Google Scholar
• Hansen JM, de Jong MF, Wu Q, et al. Pathogenic ubiquitination of GSDMB inhibits NK cell bactericidal functions. Cell. 2021;184(12):3178–3191 e18. doi: 10.1016/j.cell.2021.04.036
   PubMed Web of Science ®Google Scholar
• Li P, Jiang W, Yu Q, et al. Ubiquitination and degradation of GBPs by a Shigella effector to suppress host defence. Nature. 2017;551(7680):378–383. doi: 10.1038/nature24467
   PubMed Web of Science ®Google Scholar
• Fraser DW, Tsai TR, Orenstein W, et al. Legionnaires’ disease: description of an epidemic of pneumonia. N Engl J Med. 1977;297(22):1189–1197. doi: 10.1056/NEJM197712012972201
   PubMed Web of Science ®Google Scholar
• Qiu J, Luo ZQ. Legionella and Coxiella effectors: strength in diversity and activity. Nat Rev Microbiol. 2017;15(10):591–605. doi: 10.1038/nrmicro.2017.67
   PubMed Web of Science ®Google Scholar
• Tomaskovic I, Gonzalez A, Dikic I. Ubiquitin and Legionella: from bench to bedside. Semin Cell Dev Biol. 2022;132:230–241. doi: 10.1016/j.semcdb.2022.02.008
   PubMed Web of Science ®Google Scholar
• Hsu F, Luo X, Qiu J, et al. The legionella effector SidC defines a unique family of ubiquitin ligases important for bacterial phagosomal remodeling. Proc Natl Acad Sci U S A. 2014;111(29):10538–10543. doi: 10.1073/pnas.1402605111
   PubMed Web of Science ®Google Scholar
• Qiu J, Sheedlo MJ, Yu K, et al. Ubiquitination independent of E1 and E2 enzymes by bacterial effectors. Nature. 2016;533(7601):120–124. doi: 10.1038/nature17657
   PubMed Web of Science ®Google Scholar
• Bhogaraju S, Kalayil S, Liu Y, et al. Phosphoribosylation of ubiquitin promotes serine ubiquitination and impairs conventional ubiquitination. Cell. 2016;167(6):1636–1649 e13. doi: 10.1016/j.cell.2016.11.019
   PubMed Web of Science ®Google Scholar
• Kotewicz KM, Ramabhadran V, Sjoblom N, et al. A single legionella effector catalyzes a multistep ubiquitination pathway to rearrange tubular endoplasmic reticulum for replication. Cell Host Microbe. 2017;21(2):169–181. doi: 10.1016/j.chom.2016.12.007
   PubMed Web of Science ®Google Scholar
• Gan N, Zhen X, Liu Y, et al. Regulation of phosphoribosyl ubiquitination by a calmodulin-dependent glutamylase. Nature. 2019;572(7769):387–391. doi: 10.1038/s41586-019-1439-1
   PubMed Web of Science ®Google Scholar
• Song L, Xie Y, Li C, et al. The legionella effector SdjA is a bifunctional enzyme that distinctly regulates phosphoribosyl ubiquitination. MBio. 2021;12(5):e0231621. doi: 10.1128/mBio.02316-21
   PubMed Web of Science ®Google Scholar
• Bhogaraju S, Bonn F, Mukherjee R, et al. Inhibition of bacterial ubiquitin ligases by SidJ-calmodulin catalysed glutamylation. Nature. 2019;572(7769):382–386. doi: 10.1038/s41586-019-1440-8
   PubMed Web of Science ®Google Scholar
• Black MH, Osinski A, Gradowski M, et al. Bacterial pseudokinase catalyzes protein polyglutamylation to inhibit the SidE-family ubiquitin ligases. Science. 2019;364(6442):787–792. doi: 10.1126/science.aaw7446
   PubMed Web of Science ®Google Scholar
• Sulpizio A, Minelli ME, Wan M, et al. Protein polyglutamylation catalyzed by the bacterial calmodulin-dependent pseudokinase SidJ. Elife. 2019;8:e51162. doi: 10.7554/eLife.51162
   PubMed Web of Science ®Google Scholar
• Wan M, Sulpizio AG, Akturk A, et al. Deubiquitination of phosphoribosyl-ubiquitin conjugates by phosphodiesterase-domain-containing legionella effectors. Proc Natl Acad Sci U S A. 2019;116(47):23518–23526. doi: 10.1073/pnas.1916287116
   PubMed Web of Science ®Google Scholar
• Shin D, Mukherjee R, Liu Y, et al. Regulation of phosphoribosyl-linked serine ubiquitination by Deubiquitinases DupA and DupB. Mol Cell. 2020;77(1):164–179 e6. doi: 10.1016/j.molcel.2019.10.019
   PubMed Web of Science ®Google Scholar
• Mevissen TE, Hospenthal MK, Geurink PP, et al. OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell. 2013;154(1):169–184. doi: 10.1016/j.cell.2013.05.046
   PubMed Web of Science ®Google Scholar
• Goncharov T, Niessen K, de Almagro MC, et al. OTUB1 modulates c-IAP1 stability to regulate signalling pathways. Embo J. 2013;32(8):1103–1114. doi: 10.1038/emboj.2013.62
   PubMed Web of Science ®Google Scholar
• Zhao L, Wang X, Yu Y, et al. OTUB1 protein suppresses mTOR complex 1 (mTORC1) activity by deubiquitinating the mTORC1 inhibitor DEPTOR. J Biol Chem. 2018;293(13):4883–4892. doi: 10.1074/jbc.M117.809533
   PubMed Web of Science ®Google Scholar
• Herhaus L, Al-Salihi M, Macartney T, et al. OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3. Nat Commun. 2013;4(1):2519. doi: 10.1038/ncomms3519
   PubMedGoogle Scholar
• Wu M, Sun L, Song T. OTUB1-mediated inhibition of ubiquitination: a growing list of effectors, multiplex mechanisms, and versatile functions. Front Mol Biosci. 2023;10:1261273. doi: 10.3389/fmolb.2023.1261273
   PubMed Web of Science ®Google Scholar
• Nakada S, Tai I, Panier S, et al. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature. 2010;466(7309):941–946. doi: 10.1038/nature09297
   PubMed Web of Science ®Google Scholar
• Kumari R, Kumar R, Dey AK, et al. S-Nitrosylation of OTUB1 alters its stability and Ubc13 binding. ACS Chem Neurosci. 2022;13(10):1517–1525. doi: 10.1021/acschemneuro.1c00855
   PubMed Web of Science ®Google Scholar
• Scholz CC, Rodriguez J, Pickel C, et al. FIH regulates cellular metabolism through hydroxylation of the Deubiquitinase OTUB1. PLOS Biol. 2016;14(1):e1002347. doi: 10.1371/journal.pbio.1002347
   PubMed Web of Science ®Google Scholar
• Herhaus L, Perez-Oliva AB, Cozza G, et al. Casein kinase 2 (CK2) phosphorylates the deubiquitylase OTUB1 at Ser16 to trigger its nuclear localization. Sci Signal. 2015;8(372):ra35. doi: 10.1126/scisignal.aaa0441
   PubMed Web of Science ®Google Scholar
• Ragaz C, Pietsch H, Urwyler S, et al. The legionella pneumophila phosphatidylinositol-4 phosphate-binding type IV substrate SidC recruits endoplasmic reticulum vesicles to a replication-permissive vacuole. Cell Microbiol. 2008;10(12):2416–2433. doi: 10.1111/j.1462-5822.2008.01219.x
   PubMed Web of Science ®Google Scholar
• Horenkamp FA, Mukherjee S, Alix E, et al. Legionella pneumophila subversion of host vesicular transport by SidC effector proteins. Traffic. 2014;15(5):488–499. doi: 10.1111/tra.12158
   PubMed Web of Science ®Google Scholar
• Jeng EE, Bhadkamkar V, Ibe NU, et al. Systematic identification of Host cell regulators of legionella pneumophila pathogenesis using a genome-wide CRISPR screen. Cell Host Microbe. 2019;26(4):551–563 e6. doi: 10.1016/j.chom.2019.08.017
   PubMed Web of Science ®Google Scholar
• Lin YH, Lucas M, Evans TR, et al. RavN is a member of a previously unrecognized group of legionella pneumophila E3 ubiquitin ligases. PLOS Pathog. 2018;14(2):e1006897. doi: 10.1371/journal.ppat.1006897
   PubMed Web of Science ®Google Scholar
• Li S, Zheng H, Mao AP, et al. Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6. J Biol Chem. 2010;285(7):4291–4297. doi: 10.1074/jbc.M109.074971
   PubMed Web of Science ®Google Scholar
• Ivanov SS, Roy CR. Pathogen signatures activate a ubiquitination pathway that modulates the function of the metabolic checkpoint kinase mTOR. Nat Immunol. 2013;14(12):1219–1228. doi: 10.1038/ni.2740
   PubMed Web of Science ®Google Scholar
• De Leon JA, Qiu J, Nicolai CJ, et al. Positive and Negative Regulation of the Master Metabolic Regulator mTORC1 by two families of legionella pneumophila effectors. Cell Rep. 2017;21(8):2031–2038. doi: 10.1016/j.celrep.2017.10.088
   PubMed Web of Science ®Google Scholar
• Feng YY, Chen Y, Wu XY, et al. Interplay of energy metabolism and autophagy. Autophagy. 2024;20(1):4–14. doi: 10.1080/15548627.2023.2247300
   PubMed Web of Science ®Google Scholar
• Choy A, Dancourt J, Mugo B, et al. The legionella effector RavZ inhibits Host autophagy through irreversible Atg8 deconjugation. Science. 2012;338(6110):1072–1076. doi: 10.1126/science.1227026
   PubMed Web of Science ®Google Scholar
• Liu S, Luo J, Zhen X, et al. Interplay between bacterial deubiquitinase and ubiquitin E3 ligase regulates ubiquitin dynamics on legionella phagosomes. Elife. 2020;9:e58114. doi: 10.7554/eLife.58114
   PubMed Web of Science ®Google Scholar
• Bialas J, Boehm AN, Catone N, et al. The ubiquitin-like modifier FAT10 stimulates the activity of deubiquitylating enzyme OTUB1. J Biol Chem. 2019;294(12):4315–4330. doi: 10.1074/jbc.RA118.005406
   PubMed Web of Science ®Google Scholar
• Jahan AS, Biquand E, Munoz-Moreno R, et al. OTUB1 is a Key Regulator of RIG-I-Dependent Immune Signaling and is targeted for proteasomal degradation by influenza a NS1. Cell Rep. 2020;30(5):1570–1584 e6. doi: 10.1016/j.celrep.2020.01.015
   PubMed Web of Science ®Google Scholar
• Juris SJ, Shah K, Shokat K, et al. Identification of otubain 1 as a novel substrate for the yersinia protein kinase using chemical genetics and mass spectrometry. FEBS Lett. 2006;580(1):179–183. doi: 10.1016/j.febslet.2005.11.071
   PubMed Web of Science ®Google Scholar
• Price CT, Al-Quadan T, Santic M, et al. Host proteasomal degradation generates amino acids essential for intracellular bacterial growth. Science. 2011;334(6062):1553–1557. doi: 10.1126/science.1212868
   PubMed Web of Science ®Google Scholar
• Belyi Y, Levanova N, Schroeder GN. Glycosylating effectors of legionella pneumophila: finding the sweet spots for Host cell subversion. Biomolecules. 2022;12(2):255. doi: 10.3390/biom12020255
   PubMed Web of Science ®Google Scholar
• Fontana MF, Banga S, Barry KC, et al. Secreted bacterial effectors that inhibit host protein synthesis are critical for induction of the innate immune response to virulent legionella pneumophila. PLOS Pathog. 2011;7(2):e1001289. doi: 10.1371/journal.ppat.1001289
   PubMed Web of Science ®Google Scholar
• Shen X, Banga S, Liu Y, et al. Targeting eEF1A by a legionella pneumophila effector leads to inhibition of protein synthesis and induction of host stress response. Cell Microbiol. 2009;11(6):911–926. doi: 10.1111/j.1462-5822.2009.01301.x
   PubMed Web of Science ®Google Scholar
• Barry KC, Fontana MF, Portman JL, et al. IL-1alpha signaling initiates the inflammatory response to virulent legionella pneumophila in vivo. J Immunol. 2013;190(12):6329–6339. doi: 10.4049/jimmunol.1300100
   PubMed Web of Science ®Google Scholar
• Moss SM, Taylor IR, Ruggero D, et al. A legionella pneumophila kinase phosphorylates the Hsp70 chaperone family to inhibit eukaryotic protein synthesis. Cell Host Microbe. 2019;25(3):454–462 e6. doi: 10.1016/j.chom.2019.01.006
   PubMed Web of Science ®Google Scholar
• Beck WHJ, Kim D, Das J, et al. Glucosylation by the legionella effector SetA promotes the nuclear localization of the transcription factor TFEB. iScience. 2020;23(7):101300. doi: 10.1016/j.isci.2020.101300
   PubMed Web of Science ®Google Scholar
• Conover GM, Derre I, Vogel JP, et al. The legionella pneumophila LidA protein: a translocated substrate of the Dot/Icm system associated with maintenance of bacterial integrity. Mol Microbiol. 2003;48(2):305–321. doi: 10.1046/j.1365-2958.2003.03400.x
   PubMed Web of Science ®Google Scholar
• Berger KH, Isberg RR. Two distinct defects in intracellular growth complemented by a single genetic locus in legionella pneumophila. Mol Microbiol. 1993;7(1):7–19. doi: 10.1111/j.1365-2958.1993.tb01092.x
   PubMed Web of Science ®Google Scholar
• Sheedlo MJ, Qiu J, Tan Y, et al. Structural basis of substrate recognition by a bacterial deubiquitinase important for dynamics of phagosome ubiquitination. Proc Natl Acad Sci U S A. 2015;112(49):15090–15095. doi: 10.1073/pnas.1514568112
   PubMed Web of Science ®Google Scholar
• Li G, Liu H, Luo ZQ, et al. Modulation of phagosome phosphoinositide dynamics by a legionella phosphoinositide 3-kinase. EMBO Rep. 2021;22(3):e51163. doi: 10.15252/embr.202051163
   PubMed Web of Science ®Google Scholar