Rise of Bacterial Small Proteins and Peptides in Therapeutic Applications

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Abstract

Background: Polypeptides that comprise less than 100 amino acids (50 amino acids in some cases) are referred to as small proteins (SPs), however, as of date, there is no strict definition. In contrast to the small polypeptides that arise due to proteolytic activity or abrupt protein synthesis, SPs are coded by small open reading frames (sORFs) and are conventionally synthesized by ribosomes.

Purpose of the Review: Although proteins that contain more than 100 amino acids have been studied exquisitely, studies on small proteins have been largely ignored, basically due to the unsuccessful detection of these SPs by traditional methodologies/techniques. Serendipitous observation of several small proteins and elucidation of their vital functions in cellular processes opened the floodgate of a new area of research on the new family of proteins called "Small proteins". Having known the significance of such SPs, several advanced techniques are being developed to precisely identify and characterize them.

Conclusion: Bacterial small proteins (BSPs) are being intensely investigated in recent days and that has brought the versatile role of BSPs into the limelight. In particular, identification of the fact that BSPs exhibit antimicrobial activity has further expanded its scope in the area of therapeutics. Since the microbiome plays an inevitable role in determining the outcome of personalized medicine, studies on the secretory small proteins of the microbiome are gaining momentum. This review discusses the importance of bacterial small proteins and peptides in terms of their therapeutic applications.

Graphical Abstract

[1]
Storz, G.; Wolf, Y.I.; Ramamurthi, K.S. Small proteins can no longer be ignored. Annu. Rev. Biochem., 2014, 83(1), 753-777.
[http://dx.doi.org/10.1146/annurev-biochem-070611-102400] [PMID: 24606146]
[2]
Chen, J.; Brunner, A.D.; Cogan, J.Z.; Nuñez, J.K.; Fields, A.P.; Adamson, B.; Itzhak, D.N.; Li, J.Y.; Mann, M.; Leonetti, M.D.; Weissman, J.S. Pervasive functional translation of noncanonical human open reading frames. Science, 2020, 367(6482), 1140-1146.
[http://dx.doi.org/10.1126/science.aay0262] [PMID: 32139545]
[3]
Hemm, M.R.; Weaver, J.; Storz, G. Escherichia coli small proteome. Ecosal Plus, 2020, 9(1), ecosalplus.ESP-0031-2019.
[http://dx.doi.org/10.1128/ecosalplus.ESP-0031-2019] [PMID: 32385980]
[4]
Hobbs, E.C.; Fontaine, F.; Yin, X.; Storz, G. An expanding universe of small proteins. Curr. Opin. Microbiol., 2011, 14(2), 167-173.
[http://dx.doi.org/10.1016/j.mib.2011.01.007] [PMID: 21342783]
[5]
Ramamurthi, K.S.; Storz, G. The small protein floodgates are opening; now the functional analysis begins. BMC Biol., 2014, 12(1), 96.
[http://dx.doi.org/10.1186/s12915-014-0096-y] [PMID: 25475548]
[6]
Shapiro, L.; McAdams, H.H.; Losick, R. Why and how bacteria localize proteins. Science, 2009, 326(5957), 1225-1228.
[http://dx.doi.org/10.1126/science.1175685] [PMID: 19965466]
[7]
Lloyd, C.R.; Park, S.; Fei, J.; Vanderpool, C.K. The small protein sgrt controls transport activity of the glucose-specific phosphotransferase system. J. Bacteriol., 2017, 199(11), e00869-e16.
[http://dx.doi.org/10.1128/JB.00869-16] [PMID: 28289085]
[8]
Basrai, M.A.; Hieter, P.; Boeke, J.D. Small open reading frames: Beautiful needles in the haystack. Genome Res., 1997, 7(8), 768-771.
[http://dx.doi.org/10.1101/gr.7.8.768] [PMID: 9267801]
[9]
Duval, M.; Cossart, P. Small bacterial and phagic proteins: An updated view on a rapidly moving field. Curr. Opin. Microbiol., 2017, 39, 81-88.
[http://dx.doi.org/10.1016/j.mib.2017.09.010] [PMID: 29111488]
[10]
Brandenburg, F.; Klähn, S. Small but smart: On the diverse role of small proteins in the regulation of cyanobacterial metabolism. Life, 2020, 10(12), 322.
[http://dx.doi.org/10.3390/life10120322] [PMID: 33271798]
[11]
Yang, X.; Tschaplinski, T.J.; Hurst, G.B.; Jawdy, S.; Abraham, P.E.; Lankford, P.K.; Adams, R.M.; Shah, M.B.; Hettich, R.L.; Lindquist, E.; Kalluri, U.C.; Gunter, L.E.; Pennacchio, C.; Tuskan, G.A. Discovery and annotation of small proteins using genomics, proteomics, and computational approaches. Genome Res., 2011, 21(4), 634-641.
[http://dx.doi.org/10.1101/gr.109280.110] [PMID: 21367939]
[12]
Zaslavsky, L.; Ciufo, S.; Fedorov, B.; Tatusova, T. Clustering analysis of proteins from microbial genomes at multiple levels of resolution. BMC .bioinfo., 2016, 17(8), 545-552.
[13]
Miravet-Verde, S.; Ferrar, T.; Espadas-García, G.; Mazzolini, R.; Gharrab, A.; Sabido, E.; Serrano, L.; Lluch-Senar, M. Unraveling the hidden universe of small proteins in bacterial genomes. Mol. Syst. Biol., 2019, 15(2), e8290.
[http://dx.doi.org/10.15252/msb.20188290] [PMID: 30796087]
[14]
Hemm, M.R.; Paul, B.J.; Miranda-Ríos, J.; Zhang, A.; Soltanzad, N.; Storz, G. Small stress response proteins in Escherichia coli: Proteins missed by classical proteomic studies. J. Bacteriol., 2010, 192(1), 46-58.
[http://dx.doi.org/10.1128/JB.00872-09] [PMID: 19734316]
[15]
Sberro, H.; Fremin, B.J.; Zlitni, S.; Edfors, F.; Greenfield, N.; Snyder, M.P.; Pavlopoulos, G.A.; Kyrpides, N.C.; Bhatt, A.S. Large-scale analyses of human microbiomes reveal thousands of small, novel genes. Cell, 2019, 178(5), 1245-1259.e14.
[http://dx.doi.org/10.1016/j.cell.2019.07.016] [PMID: 31402174]
[16]
Fritsch, C.; Herrmann, A.; Nothnagel, M.; Szafranski, K.; Huse, K.; Schumann, F.; Schreiber, S.; Platzer, M.; Krawczak, M.; Hampe, J.; Brosch, M. Genome-wide search for novel human uORFs and N-terminal protein extensions using ribosomal footprinting. Genome Res., 2012, 22(11), 2208-2218.
[http://dx.doi.org/10.1101/gr.139568.112] [PMID: 22879431]
[17]
Keseler, I.M.; Collado-Vides, J.; Santos-Zavaleta, A.; Peralta-Gil, M.; Gama-Castro, S.; Muñiz-Rascado, L.; Bonavides-Martinez, C.; Paley, S.; Krummenacker, M.; Altman, T.; Kaipa, P.; Spaulding, A.; Pacheco, J.; Latendresse, M.; Fulcher, C.; Sarker, M.; Shearer, A.G.; Mackie, A.; Paulsen, I.; Gunsalus, R.P.; Karp, P.D. EcoCyc: A comprehensive database of Escherichia coli biology. Nucleic Acids Res., 2011, 39(Database), D583-D590.
[http://dx.doi.org/10.1093/nar/gkq1143] [PMID: 21097882]
[18]
Hao, Y.; Zhang, L.; Niu, Y.; Cai, T.; Luo, J.; He, S.; Zhang, B.; Zhang, D.; Qin, Y.; Yang, F.; Chen, R. SmProt: A database of small proteins encoded by annotated coding and non-coding RNA loci. Brief. Bioinform., 2018, 19(4), 636-643.
[PMID: 28137767]
[19]
Lease, K.A.; Walker, J.C. Bioinformatic identification of plant peptides in Peptidomics; Humana Pres: USA, 2010, pp. 375-383.
[http://dx.doi.org/10.1007/978-1-60761-535-4_26]
[20]
Fontaine, F.; Fuchs, R.T.; Storz, G. Membrane localization of small proteins in Escherichia coli. J. Biol. Chem., 2011, 286(37), 32464-32474.
[http://dx.doi.org/10.1074/jbc.M111.245696] [PMID: 21778229]
[21]
Steinberg, R.; Koch, H.G. The largely unexplored biology of small proteins in pro- and eukaryotes. FEBS J., 2021, 288(24), 7002-7024.
[http://dx.doi.org/10.1111/febs.15845] [PMID: 33780127]
[22]
Science Daily. Revealing the role of the mysterious small proteins., Available from: www.science daily.com (Accessed on: February 22, 2019)
[23]
Ursell, L.K.; Metcalf, J.L.; Parfrey, L.W.; Knight, R. Defining the human microbiome. Nutr. Rev., 2012, 70(S1), S38-S44.
[http://dx.doi.org/10.1111/j.1753-4887.2012.00493.x] [PMID: 22861806]
[24]
Petruschke, H.; Schori, C.; Canzler, S.; Riesbeck, S.; Poehlein, A.; Daniel, R.; Frei, D.; Segessemann, T.; Zimmerman, J.; Marinos, G.; Kaleta, C.; Jehmlich, N.; Ahrens, C.H.; von Bergen, M. Discovery of novel community-relevant small proteins in a simplified human intestinal microbiome. Microbiome, 2021, 9(1), 55.
[http://dx.doi.org/10.1186/s40168-020-00981-z] [PMID: 33622394]
[25]
Fuchs, S.; Kucklick, M.; Lehmann, E.; Beckmann, A.; Wilkens, M.; Kolte, B.; Mustafayeva, A.; Ludwig, T.; Diwo, M.; Wissing, J.; Jänsch, L.; Ahrens, C.H.; Ignatova, Z.; Engelmann, S. Towards the characterization of the hidden world of small proteins in Staphylococcus aureus, a proteogenomics approach. PLoS Genet., 2021, 17(6), e1009585.
[http://dx.doi.org/10.1371/journal.pgen.1009585] [PMID: 34061833]
[26]
Garai, P.; Blanc-Potard, A. Uncovering small membrane proteins in pathogenic bacteria: Regulatory functions and therapeutic potential. Mol. Microbiol., 2020, 114(5), 710-720.
[http://dx.doi.org/10.1111/mmi.14564] [PMID: 32602138]
[27]
Stone, T.A.; Deber, C.M. Therapeutic design of peptide modulators of protein-protein interactions in membranes. Biochim. Biophys. Acta Biomembr., 2017, 1859(4), 577-585.
[http://dx.doi.org/10.1016/j.bbamem.2016.08.013] [PMID: 27580024]
[28]
Coutinho, H.M.; Lôbo, K.; Bezerra, D.C.; Lôbo, I. Peptides and proteins with antimicrobial activity. Indian J. Pharmacol., 2008, 40(1), 3-9.
[http://dx.doi.org/10.4103/0253-7613.40481] [PMID: 21264153]
[29]
Cotter, P.; Hill, C.; Ross, R. Bacterial lantibiotics: Strategies to improve therapeutic potential. Curr. Protein Pept. Sci., 2005, 6(1), 61-75.
[http://dx.doi.org/10.2174/1389203053027584] [PMID: 15638769]
[30]
Cleveland, J.; Montville, T.J.; Nes, I.F.; Chikindas, M.L. Bacteriocins: Safe, natural antimicrobials for food preservation. Int. J. Food Microbiol., 2001, 71(1), 1-20.
[http://dx.doi.org/10.1016/S0168-1605(01)00560-8] [PMID: 11764886]
[31]
Shin, J.M.; Ateia, I.; Paulus, J.R.; Liu, H.; Fenno, J.C.; Rickard, A.H.; Kapila, Y.L. Antimicrobial nisin acts against saliva derived multi-species biofilms without cytotoxicity to human oral cells. Front. Microbiol., 2015, 6, 617.
[http://dx.doi.org/10.3389/fmicb.2015.00617] [PMID: 26150809]
[32]
Joo, N.E.; Ritchie, K.; Kamarajan, P.; Miao, D.; Kapila, Y.L. Nisin, an apoptogenic bacteriocin and food preservative, attenuates HNSCC tumorigenesis via CHAC 1. Cancer Med., 2012, 1(3), 295-305.
[http://dx.doi.org/10.1002/cam4.35] [PMID: 23342279]
[33]
Karpiński, T.; Adamczak, A. Anticancer activity of bacterial proteins and peptides. Pharmaceutics, 2018, 10(2), 54.
[http://dx.doi.org/10.3390/pharmaceutics10020054] [PMID: 29710857]
[34]
Chakrabarty, A.M.; Bernardes, N.; Fialho, A.M. Bacterial proteins and peptides in cancer therapy. Bioengineered, 2014, 5(4), 234-242.
[http://dx.doi.org/10.4161/bioe.29266] [PMID: 24875003]
[35]
Zhang, Y.; Zhang, Y.; Xia, L.; Zhang, X.; Ding, X.; Yan, F.; Wu, F. Escherichia coli Nissle 1917 targets and restrains mouse B16 melanoma and 4T1 breast tumors through expression of azurin protein. Appl. Environ. Microbiol., 2012, 78(21), 7603-7610.
[http://dx.doi.org/10.1128/AEM.01390-12] [PMID: 22923405]
[36]
Tyagi, A.; Tuknait, A.; Anand, P.; Gupta, S.; Sharma, M.; Mathur, D.; Joshi, A.; Singh, S.; Gautam, A.; Raghava, G.P.S. CancerPPD: A database of anticancer peptides and proteins. Nucleic Acids Res., 2015, 43(D1), D837-D843.
[http://dx.doi.org/10.1093/nar/gku892] [PMID: 25270878]
[37]
Lago, M.; Monteil, V.; Douche, T.; Guglielmini, J.; Criscuolo, A.; Maufrais, C.; Matondo, M.; Norel, F. Proteome remodelling by the stress sigma factor RpoS/σS in Salmonella: Identification of small proteins and evidence for post-transcriptional regulation. Sci. Rep., 2017, 7(1), 2127.
[http://dx.doi.org/10.1038/s41598-017-02362-3] [PMID: 28522802]
[38]
Pichon, C.; Felden, B. Proteins that interact with bacterial small RNA regulators. FEMS Microbiol. Rev., 2007, 31(5), 614-625.
[http://dx.doi.org/10.1111/j.1574-6976.2007.00079.x] [PMID: 17655690]
[39]
Mandin, P.; Repoila, F.; Vergassola, M.; Geissmann, T.; Cossart, P. Identification of new noncoding RNAs in Listeria monocytogenes and prediction of mRNA targets. Nucleic Acids Res., 2007, 35(3), 962-974.
[http://dx.doi.org/10.1093/nar/gkl1096] [PMID: 17259222]
[40]
Sun, Y.H.; de Jong, M.F.; den Hartigh, A.B.; Roux, C.M.; Rolán, H.G.; Tsolis, R.M. The small protein CydX is required for function of cytochrome bd oxidase in Brucella abortus. Front. Cell. Infect. Microbiol., 2012, 2, 47.
[http://dx.doi.org/10.3389/fcimb.2012.00047] [PMID: 22919638]
[41]
Budnick, J.A.; Sheehan, L.M.; Kang, L.; Michalak, P.; Caswell, C.C. Characterization of three small proteins in Brucella abortus linked to fucose utilization. J. Bacteriol., 2018, 200(18), e00127-e18.
[http://dx.doi.org/10.1128/JB.00127-18] [PMID: 29967118]
[42]
Raina, M.; Storz, G. SgrT, a small protein that packs a sweet punch. J. Bacteriol., 2017, 199(11), e00130-e17.
[http://dx.doi.org/10.1128/JB.00130-17] [PMID: 28289086]
[43]
Levine, E.; Zhang, Z.; Kuhlman, T.; Hwa, T. Quantitative characteristics of gene regulation by small RNA. PLoS Biol., 2007, 5(9), e229.
[http://dx.doi.org/10.1371/journal.pbio.0050229] [PMID: 17713988]
[44]
Lee, H.M.; Ren, J.; Tran, K.M.; Jeon, B.M.; Park, W.U.; Kim, H.; Lee, K.E.; Oh, Y.; Choi, M.; Kim, D.S.; Na, D. Identification of efficient prokaryotic cell-penetrating peptides with applications in bacterial biotechnology. Commun. Biol., 2021, 4(1), 205.
[http://dx.doi.org/10.1038/s42003-021-01726-w] [PMID: 33589718]
[45]
Gil-Cruz, C.; Perez-Shibayama, C.; De Martin, A.; Ronchi, F.; Van Der Borght, K.; Niederer, R.; Onder, L.; Lütge, M.; Novkovic, M.; Nindl, V.; Ramos, G. Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy. Science, 2019, 366(6467), 881-886.
[http://dx.doi.org/10.1126/science.aav3487]
[46]
Sajid, M.; Biswas, K.; Singh, H.; Negi, S. Auto-reactivity against gut bacterial peptides in patients with late-onset diabetes. Autoimmunity, 2020, 53(7), 385-393.
[http://dx.doi.org/10.1080/08916934.2020.1818232]
[47]
Wynendaele, E.; Verbeke, F.; Stalmans, S.; Gevaert, B.; Janssens, Y.; Van De Wiele, C.; Peremans, K.; Burvenich, C.; De Spiegeleer, B. Quorum sensing peptides selectively penetrate the blood-brain barrier. PLoS One, 2015, 10(11), e0142071.
[http://dx.doi.org/10.1371/journal.pone.0142071] [PMID: 26536593]
[48]
Finegold, S.M.; Molitoris, D.; Song, Y.; Liu, C.; Vaisanen, M.L.; Bolte, E.; McTeague, M.; Sandler, R.; Wexler, H.; Marlowe, E.M.; Collins, M.D.; Lawson, P.A.; Summanen, P.; Baysallar, M.; Tomzynski, T.J.; Read, E.; Johnson, E.; Rolfe, R.; Nasir, P.; Shah, H.; Haake, D.A.; Manning, P.; Kaul, A. Gastrointestinal microflora studies in late-onset autism. Clin. Infect. Dis., 2002, 35(Suppl. 1), S6-S16.
[http://dx.doi.org/10.1086/341914] [PMID: 12173102]
[49]
Luna, R.A.; Foster, J.A. Gut brain axis: Diet microbiota interactions and implications for modulation of anxiety and depression. Curr. Opin. Biotechnol., 2015, 32, 35-41.
[http://dx.doi.org/10.1016/j.copbio.2014.10.007] [PMID: 25448230]
[50]
Janssens, Y.; Wynendaele, E.; Verbeke, F.; Debunne, N.; Gevaert, B.; Audenaert, K.; Van DeWiele, C.; De Spiegeleer, B. Screening of quorum sensing peptides for biological effects in neuronal cells. Peptides, 2018, 101(101), 150-156.
[http://dx.doi.org/10.1016/j.peptides.2018.01.013] [PMID: 29360479]
[51]
Kang, C.K.; Jayasinha, V.; Martin, P.T. Identification of peptides that specifically bind Aβ1-40 amyloid in vitro and amyloid plaques in Alzheimer’s disease brain using phage display. Neurobiol. Dis., 2003, 14(1), 146-156.
[http://dx.doi.org/10.1016/S0969-9961(03)00105-0] [PMID: 13678675]
[52]
Krauspe, V.; Fahrner, M.; Spät, P.; Steglich, C.; Frankenberg-Dinkel, N. Maček, B.; Schilling, O.; Hess, W.R. Discovery of a small protein factor involved in the coordinated degradation of phycobilisomes in cyanobacteria. Proc. Natl. Acad. Sci., 2021, 118(5), e2012277118.
[http://dx.doi.org/10.1073/pnas.2012277118] [PMID: 33509926]
[53]
Venturini, E.; Svensson, S. L.; Maaß, S.; Gelhausen, R.; Eggenhofer, F.; Li, L.; Cain, A. K. A global data-driven census of Salmonella small proteins and their potential functions in bacterial virulence. microLife., 2020, 1(1)
[http://dx.doi.org/10.1093/femsml/uqaa002]
[54]
Impens, F.; Rolhion, N.; Radoshevich, L.; Bécavin, C.; Duval, M.; Mellin, J.; García del Portillo, F.; Pucciarelli, M.G.; Williams, A.H.; Cossart, P. N-terminomics identifies Prli42 as a membrane miniprotein conserved in Firmicutes and critical for stressosome activation in Listeria monocytogenes. Nat. Microbiol., 2017, 2(5), 17005.
[http://dx.doi.org/10.1038/nmicrobiol.2017.5] [PMID: 28191904]
[55]
Wu, W.; Jin, S. PtrB of Pseudomonas aeruginosa suppresses the type III secretion system under the stress of DNA damage. J. Bacteriol., 2005, 187(17), 6058-6068.
[http://dx.doi.org/10.1128/JB.187.17.6058-6068.2005] [PMID: 16109947]
[56]
Sayed, N.; Nonin-Lecomte, S.; Réty, S.; Felden, B. Functional and structural insights of a Staphylococcus aureus apoptotic-like membrane peptide from a toxin-antitoxin module. J. Biol. Chem., 2012, 287(52), 43454-43463.
[http://dx.doi.org/10.1074/jbc.M112.402693] [PMID: 23129767]
[57]
Shankar, M.; Hossain, M.S.; Biswas, I. Pleiotropic regulation of virulence genes in Streptococcus mutans by the conserved small protein SprV. J. Bacteriol., 2017, 199(8), e00847-e16.
[http://dx.doi.org/10.1128/JB.00847-16] [PMID: 28167518]
[58]
Schmalisch, M.; Maiques, E.; Nikolov, L.; Camp, A.H.; Chevreux, B.; Muffler, A.; Rodriguez, S.; Perkins, J.; Losick, R. Small genes under sporulation control in the Bacillus subtilis genome. J. Bacteriol., 2010, 192(20), 5402-5412.
[http://dx.doi.org/10.1128/JB.00534-10] [PMID: 20709900]