Abstract
In addition to the extracellular proteins secreted by known secretory pathways, a number of cytoplasmic proteins without predicable or known signal sequences or secretory motifs have been found in the extracellular milieu, and were consequently classified as non-classically secreted proteins. Non-classical protein secretion is considered to be a general, conserved cellular phenomenon in both eukaryotes and prokaryotes. There are several research hotspots on the non-classical protein secretory pathway, and the most important two of them are the recognition principle of substrate proteins and possible secretory mechanisms. To date, researchers have made some progress in understanding the characteristics of these proteins. For example, it was discovered that many non-classically secreted proteins exist and are secreted in multimeric form. Some of these proteins prefer to be clustered and exported at the poles and the septum of the cell. The majority of these proteins play different functions when they are in the intra- and extracellular environments, and several of their functions are related to survival and pathogenicity. Furthermore, non-classically secreted proteins can be used as leading proteins to guide a POI (protein of interest) out of the cells, which provides a novel strategy for protein secretion with potential applications in the industry. Summarizing these findings, this review emphasizes the hot spots related to non-classically secreted proteins in bacteria, lists the most important hypotheses on the selection and secretion mechanisms of non-classically secreted proteins, and put forward their potential applications.
Similar content being viewed by others
References
Antelmann H, Tjalsma H, Voigt B, Ohlmeier S, Bron S, van Dijl JM, Hecker M (2001) A proteomic view on genome-based signal peptide predictions. Genome Res 11(9):1484–1502. https://doi.org/10.1101/gr.182801
Antelmann H, van Dijl JM, Bron S, Hecker M (2005) Proteomic survey through secretome of Bacillus subtilis. Methods Biochem Anal 49(1):179–208. https://doi.org/10.1002/0471973165.ch12
Bandyopadhyay P, Steinman HM (2000) Catalase-peroxidases of Legionella pneumophila: cloning of the katA gene and studies of KatA function. J Bacteriol 182(23):6679–6686. https://doi.org/10.1128/jb.182.23.6679-6686.2000
Beck HC, Madsen SM, Glenting J, Petersen J, Israelsen H, Norrelykke MR, Antonsson M, Hansen AM (2009) Proteomic analysis of cell surface-associated proteins from probiotic Lactobacillus plantarum. FEMS Microbiol Lett 297(1):61–66. https://doi.org/10.1111/j.1574-6968.2009.01662.x
Bendtsen JD, Jensen LJ, Blom N, Von Heijne G, Brunak S (2004) Feature-based prediction of non-classical and leaderless protein secretion. Protein Eng Des Sel 17(4):349–356. https://doi.org/10.1093/protein/gzh037
Bendtsen JD, Kiemer L, Fausboll A, Brunak S (2005) Non-classical protein secretion in bacteria. BMC Microbiol 5:58. https://doi.org/10.1186/1471-2180-5-58
Bishop DG, Work E (1965) An extracellular glycolipid produced by Escherichia coli grown under lysine-limiting conditions. Biochem J 96(2):567–576. https://doi.org/10.1042/bj09060567
Braunstein M, Brown AM, Kurtz S, Jacobs WR Jr (2001) Two nonredundant SecA homologues function in mycobacteria. J Bacteriol 183(24):6979–6990. https://doi.org/10.1128/JB.183.24.6979-6990.2001
Braunstein M, Espinosa BJ, Chan J, Belisle JT, Jacobs WR Jr (2003) SecA2 functions in the secretion of superoxide dismutase a and in the virulence of Mycobacterium tuberculosis. Mol Microbiol 48(2):453–464. https://doi.org/10.1046/j.1365-2958.2003.03438.x
Brodin P, Rosenkrands I, Andersen P, Cole ST, Brosch R (2004) ESAT-6 proteins: protective antigens and virulence factors? Trends Microbiol 12(11):500–508. https://doi.org/10.1016/j.tim.2004.09.007
Burts ML, Williams WA, DeBord K, Missiakas DM (2005) EsxA and EsxB are secreted by an ESAT-6-like system that is required for the pathogenesis of Staphylococcus aureus infections. Proc Natl Acad Sci 102(4):1169–1174. https://doi.org/10.1073/pnas.0405620102
Callahan B, Nguyen K, Collins A, Valdes K, Caplow M, Crossman DK, Steyn AJ, Eisele L, Derbyshire KM (2010) Conservation of structure and protein-protein interactions mediated by the secreted mycobacterial proteins EsxA, EsxB, and EspA. J Bacteriol 192(1):326–335. https://doi.org/10.1128/JB.01032-09
Candela M, Centanni M, Fiori J, Biagi E, Turroni S, Orrico C, Bergmann S, Hammerschmidt S, Brigidi P (2010) DnaK from Bifidobacterium animalis subsp. lactis is a surface-exposed human plasminogen receptor upregulated in response to bile salts. Microbiology 156(Pt 6):1609–1618. https://doi.org/10.1099/mic.0.038307-0
Chen J, Zhao L, Fu G, Zhou W, Sun Y, Zheng P, Sun J, Zhang D (2016) A novel strategy for protein production using non-classical secretion pathway in Bacillus subtilis. Microb Cell Factories 15(1):1–16. https://doi.org/10.1186/s12934-016-0469-8
Cui J, Wang G, Chen H, Chen J, Gu Z, Chen W, Zhang H (2015) Effect of non-classical secreted proteins on LipaseA secretion. Acta Microbiol Sin 55(2):198–204
Deatherage BL, Cookson BT (2012) Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life. Infect Immun 80(6):1948–1957. https://doi.org/10.1128/IAI.06014-11
Dreisbach A, Hempel K, Buist G, Hecker M, Becher D, van Dijl JM (2010) Profiling the surfacome of Staphylococcus aureus. Proteomics 10(17):3082–3096. https://doi.org/10.1002/pmic.201000062
Driessen AJ, Manting EH, van der Does C (2001) The structural basis of protein targeting and translocation in bacteria. Nat Struct Biol 8(6):492–498. https://doi.org/10.1038/88549
Ebner P, Prax M, Nega M, Koch I, Dube L, Yu W, Rinker J, Popella P, Flotenmeyer M, Gotz F (2015) Excretion of cytoplasmic proteins (ECP) in Staphylococcus aureus. Mol Microbiol 97(4):775–789. https://doi.org/10.1111/mmi.13065
Ebner P, Rinker J, Gotz F (2016a) Excretion of cytoplasmic proteins in Staphylococcus is most likely not due to cell lysis. Curr Genet 62(1):19–23. https://doi.org/10.1007/s00294-015-0504-z
Ebner P, Rinker J, Nguyen MT, Popella P, Nega M, Luqman A, Schittek B, Di Marco M, Stevanovic S, Gotz F (2016b) Excreted cytoplasmic proteins contribute to pathogenicity in Staphylococcus aureus. Infect Immun 84(6):1672–1681. https://doi.org/10.1128/IAI.00138-16
Ebner P, Luqman A, Reichert S, Hauf K, Popella P, Forchhammer K, Otto M, Gotz F (2017) Non-classical protein excretion is boosted by PSMalpha-induced cell leakage. Cell Rep 20(6):1278–1286. https://doi.org/10.1016/j.celrep.2017.07.045
Elvekrog MM, Walter P (2015) Dynamics of co-translational protein targeting. Curr Opin Chem Biol 29:79–86. https://doi.org/10.1016/j.cbpa.2015.09.016
Gao D, Wang S, Li H, Yu H, Qi Q (2015) Identification of a heterologous cellulase and its N-terminus that can guide recombinant proteins out of Escherichia coli. Microb Cell Factories 14:49. https://doi.org/10.1186/s12934-015-0230-8
Gao D, Luan Y, Liang Q, Qi Q (2016) Exploring the N-terminal role of a heterologous protein in secreting out of Escherichia coli. Biotechnol Bioeng 113(12):2561–2567. https://doi.org/10.1002/bit.26028
Georgiou G, Valax P (1996) Expression of correctly folded proteins in Escherichia coli. Curr Opin Biotechnol 7(2):190–197. https://doi.org/10.1016/s0958-1669(96)80012-7
Gotz F, Yu W, Dube L, Prax M, Ebner P (2015) Excretion of cytosolic proteins (ECP) in bacteria. Int J Med Microbiol : IJMM 305(2):230–237. https://doi.org/10.1016/j.ijmm.2014.12.021
Govind R, Dupuy B (2012) Secretion of Clostridium difficile toxins A and B requires the holin-like protein TcdE. PLoS Pathog 8(6):e1002727. https://doi.org/10.1371/journal.ppat.1002727
Guinn KM, Hickey MJ, Mathur SK, Zakel KL, Grotzke JE, Lewinsohn DM, Smith S, Sherman DR (2004) Individual RD1-region genes are required for export of ESAT-6/CFP-10 and for virulence of Mycobacterium tuberculosis. Mol Microbiol 51(2):359–370. https://doi.org/10.1046/j.1365-2958.2003.03844.x
Hamilton JJ, Marlow VL, Owen RA, Costa Mde A, Guo M, Buchanan G, Chandra G, Trost M, Coulthurst SJ, Palmer T, Stanley-Wall NR, Sargent F (2014) A holin and an endopeptidase are essential for chitinolytic protein secretion in Serratia marcescens. J Cell Biol 207(5):615–626. https://doi.org/10.1083/jcb.201404127
Harth G, Horwitz MA (1997) Expression and efficient export of enzymatically active Mycobacterium tuberculosis glutamine synthetase in Mycobacterium smegmatis and evidence that the information for export is contained within the protein. J Biol Chem 272(36):22728–22735. https://doi.org/10.1074/jbc.272.36.22728
Harth G, Horwitz MA (1999) Export of recombinant Mycobacterium tuberculosis superoxide dismutase is dependent upon both information in the protein and mycobacterial export machinery. A model for studying export of leaderless proteins by pathogenic mycobacteria. J Biol Chem 274(7):4281–4292. https://doi.org/10.1074/jbc.274.7.4281
Harth G, Clemens DL, Horwitz MA (1994) Glutamine synthetase of Mycobacterium tuberculosis: extracellular release and characterization of its enzymatic activity. Proc Natl Acad Sci U S A 91(20):9342–9346. https://doi.org/10.1073/pnas.91.20.9342
Hughes MJG (2002) Identification of major outer surface proteins of Streptococcus agalactiae. Infect Immun 70(3):1254–1259. https://doi.org/10.1128/iai.70.3.1254-1259.2002
Jeiranikhameneh M, Razavi MR, Irani S, Siadat SD, Oloomi M (2017) Designing novel construction for cell surface display of protein E on Escherichia coli using non-classical pathway based on Lpp-OmpA. AMB Express 7(1). https://doi.org/10.1186/s13568-017-0350-0
Katakura Y, Sano R, Hashimoto T, Ninomiya K, Shioya S (2010) Lactic acid bacteria display on the cell surface cytosolic proteins that recognize yeast mannan. Appl Microbiol Biotechnol 86(1):319–326. https://doi.org/10.1007/s00253-009-2295-y
Kouwen TR, Antelmann H, van der Ploeg R, Denham EL, Hecker M, van Dijl JM (2009) MscL of Bacillus subtilis prevents selective release of cytoplasmic proteins in a hypotonic environment. Proteomics 9(4):1033–1043. https://doi.org/10.1002/pmic.200800483
Kudva R, Denks K, Kuhn P, Vogt A, Muller M, Koch HG (2013) Protein translocation across the inner membrane of Gram-negative bacteria: the Sec and Tat dependent protein transport pathways. Res Microbiol 164(6):505–534. https://doi.org/10.1016/j.resmic.2013.03.016
Lancefield RC, McCarty M, Everly WN (1975) Multiple mouse-protective antibodies directed against group B streptococci. Special reference to antibodies effective against protein antigens. J Exp Med 142(1):165–179. https://doi.org/10.1084/jem.142.1.165
Lenz LL, Portnoy DA (2002) Identification of a second Listeria secA gene associated with protein secretion and the rough phenotype. Mol Microbiol 45(4):1043–1056. https://doi.org/10.1046/j.1365-2958.2002.03072.x
Lyu Y, Ye L, Xu J, Yang X, Chen W, Yu H (2016) Recent research progress with phospholipase C from Bacillus cereus. Biotechnol Lett 38(1):23–31. https://doi.org/10.1007/s10529-015-1962-6
Naclerio G, Baccigalupi L, Caruso C, De Felice M, Ricca E (1995) Bacillus subtilis vegetative catalase is an extracellular enzyme. Appl Environ Microbil 61(12):4471–4473. https://doi.org/10.1109/TVT..2002.804846
Natale P, Brüser T, Driessen AJM (2008) Sec- and Tat-mediated protein secretion across the bacterial cytoplasmic membrane—distinct translocases and mechanisms. Biochim Biophys Acta 1778(9):1735–1756. https://doi.org/10.1016/j.bbamem.2007.07.015
Nega M, Dube L, Kull M, Ziebandt AK, Ebner P, Albrecht D, Krismer B, Rosenstein R, Hecker M, Gotz F (2015) Secretome analysis revealed adaptive and non-adaptive responses of the Staphylococcus carnosus femB mutant. Proteomics 15(7):1268–1279. https://doi.org/10.1002/pmic.201400343
Nickel W (2003) The mystery of nonclassical protein secretion. Eur J Biochem 270(10):2109–2119. https://doi.org/10.1046/j.1432-1033.2003.03577.x
O'Connor JR, Lyras D, Farrow KA, Adams V, Powell DR, Hinds J, Cheung JK, Rood JI (2006) Construction and analysis of chromosomal Clostridium difficile mutants. Mol Microbiol 61(5):1335–1351. https://doi.org/10.1111/j.1365-2958.2006.05315.x
Oliveira L, Madureira P, Andrade EB, Bouaboud A, Morello E, Ferreira P, Poyart C, Trieu-Cuot P, Dramsi S (2012) Group B streptococcus GAPDH is released upon cell lysis, associates with bacterial surface, and induces apoptosis in murine macrophages. PLoS One 7(1):e29963. https://doi.org/10.1371/journal.pone.0029963
Pacheco LG, Slade SE, Seyffert N, Santos AR, Castro TL, Silva WM, Santos AV, Santos SG, Farias LM, Carvalho MA, Pimenta AM, Meyer R, Silva A, Scrivens JH, Oliveira SC, Miyoshi A, Dowson CG, Azevedo V (2011) A combined approach for comparative exoproteome analysis of Corynebacterium pseudotuberculosis. BMC Microbiol 11(1):12. https://doi.org/10.1186/1471-2180-11-12
Pallen MJ (2002) The ESAT-6/WXG100 superfamily—and a new Gram-positive secretion system? Trends Microbiol 10(5):209–212. https://doi.org/10.1016/S0966-842X(02)02345-4
Palmer T, Berks BC (2012) The twin-arginine translocation (Tat) protein export pathway. Nat Rev Microbiol 10(7):483–496. https://doi.org/10.1038/nrmicro2814
Pan X, Yang Y, Liu X, Li D, Li J, Guo X, Zhou Z (2016) Secretory expression of a heterologous protein, Aiio-AIO6BS, in Bacillus subtilis via a non-classical secretion pathway. Biochem Biophys Res Commun 478(2):881–886. https://doi.org/10.1016/j.bbrc.2016.08.045
Pancholi V, Chhatwal GS (2003) Housekeeping enzymes as virulence factors for pathogens. Int J Med Microbiol : IJMM 293(6):391–401. https://doi.org/10.1078/1438-4221-00283
Pancholi V, Fischetti VA (1992) A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. J Exp Med 176(2):415–426. https://doi.org/10.1084/jem.176.2.415
Pancholi V, Fischetti VA (1998) alpha-enolase, a novel strong plasmin(ogen) binding protein on the surface of pathogenic streptococci. J Biol Chem 273(23):14503–14515. https://doi.org/10.1074/jbc.273.23.14503
Pasztor L, Ziebandt AK, Nega M, Schlag M, Haase S, Franz-Wachtel M, Madlung J, Nordheim A, Heinrichs DE, Gotz F (2010) Staphylococcal major autolysin (Atl) is involved in excretion of cytoplasmic proteins. J Biol Chem 285(47):36794–36803. https://doi.org/10.1074/jbc.M110.167312
Rinas U, Hoffmann F, Betiku E, Estape D, Marten S (2007) Inclusion body anatomy and functioning of chaperone-mediated in vivo inclusion body disassembly during high-level recombinant protein production in Escherichia coli. J Biotechnol 127(2):244–257. https://doi.org/10.1016/j.jbiotec.2006.07.004
Rosenkrands I, Slayden RA, Crawford J, Aagaard C, Barry CEI, Andersen P (2002) Hypoxic response of Mycobacterium tuberculosis studied by metabolic labeling and proteome analysis of cellular and extracellular proteins. J Bacteriol 184(13):3485–3491. https://doi.org/10.1128/jb.184.13.3485-3491.2002
Rubartelli A, Cozzolino F, Talio M, Sitia R (1990) A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence. EMBO J 9(5):1503–1510. https://doi.org/10.1089/dna.1990.9.293
Rubartelli A, Bajetto A, Allavena G, Wollman E, Sitia R (1992) Secretion of thioredoxin by normal and neoplastic cells through a leaderless secretory pathway. J Biol Chem 267(34):24161–24164. https://doi.org/10.1016/S0022-5193(05)80731-3
Schatz G, Dobberstein B (1996) Common principles of protein translocation across membranes. Science (New York, NY) 271(5255):1519–1526. https://doi.org/10.1126/science.271.5255.1519
Schlag M, Biswas R, Krismer B, Kohler T, Zoll S, Yu W, Schwarz H, Peschel A, Gotz F (2010) Role of staphylococcal wall teichoic acid in targeting the major autolysin Atl. Mol Microbiol 75(4):864–873. https://doi.org/10.1111/j.1365-2958.2009.07007.x
Scott JR, Barnett TC (2006) Surface proteins of gram-positive bacteria and how they get there. Annu Rev Microbiol 60:397–423. https://doi.org/10.1146/annurev.micro.60.080805.142256
Seydlova G, Halada P, Fiser R, Toman O, Ulrych A, Svobodova J (2012) DnaK and GroEL chaperones are recruited to the Bacillus subtilis membrane after short-term ethanol stress. J Appl Microbiol 112(4):765–774. https://doi.org/10.1111/j.1365-2672.2012.05238.x
Smith TJ, Blackman SA, Foster SJ (2000) Autolysins of Bacillus subtilis: multiple enzymes with multiple functions. Microbiology 146(Pt 2):249–262. https://doi.org/10.1099/00221287-146-2-249
Stanley SA, Raghavan S, Hwang WW, Cox JS (2003) Acute infection and macrophage subversion by Mycobacterium tuberculosis require a specialized secretion system. Proc Natl Acad Sci U S A 100(22):13001–13006. https://doi.org/10.1073/pnas.2235593100
Su L, Woodard RW, Chen J, Wu J (2013a) Extracellular location of Thermobifida fusca cutinase expressed in Escherichia coli BL21(DE3) without mediation of a signal peptide. Appl Environ Microbil 79(14):4192–4198. https://doi.org/10.1128/aem.00239-13
Su L, Xu C, Woodard RW, Chen J, Wu J (2013b) A novel strategy for enhancing extracellular secretion of recombinant proteins in Escherichia coli. Appl Microbiol Biotechnol 97(15):6705–6713. https://doi.org/10.1007/s00253-013-4994-7
Su L, Yu L, Xu C, Wu J (2015) Extracellular expression of Thermobifida fusca cutinase with pelB signal peptide depends on more than type II secretion pathway in Escherichia coli. J Biotechnol 204:47–52. https://doi.org/10.1016/j.jbiotec.2015.03.029
Su L, Jiang Q, Yu L, Wu J (2017) Enhanced extracellular production of recombinant proteins in Escherichia coli by co-expression with Bacillus cereus phospholipase C. Microb Cell Factories 16(1):24. https://doi.org/10.1186/s12934-017-0639-3
Sundaramoorthy R, Fyfe PK, Hunter WN (2008) Structure of Staphylococcus aureus EsxA suggests a contribution to virulence by action as a transport chaperone and/or adaptor protein. J Mol Biol 383(3):603–614. https://doi.org/10.1016/j.jmb.2008.08.047
Tjalsma H, Antelmann H, Jongbloed JD, Braun PG, Darmon E, Dorenbos R, Dubois JY, Westers H, Zanen G, Quax WJ, Kuipers OP, Bron S, Hecker M, van Dijl JM (2004) Proteomics of protein secretion by Bacillus subtilis: separating the “secrets” of the secretome. Microbiol Mol Biol Rev 68(2):207–233. https://doi.org/10.1128/MMBR.68.2.207-233.2004
Tong J, Dolezal P, Selkrig J, Crawford S, Simpson AG, Noinaj N, Buchanan SK, Gabriel K, Lithgow T (2011) Ancestral and derived protein import pathways in the mitochondrion of Reclinomonas americana. Mol Biol Evol 28(5):1581–1591. https://doi.org/10.1093/molbev/msq305
Tullius MV, Harth G, Horwitz MA (2001) High extracellular levels of Mycobacterium tuberculosis glutamine synthetase and superoxide dismutase in actively growing cultures are due to high expression and extracellular stability rather than to a protein-specific export mechanism. Infect Immun 69(10):6348–6363. https://doi.org/10.1128/IAI.69.10.6348-6363.2001
von Heijne G (1998) Life and death of a signal peptide. Nature 396(6707):111–113. https://doi.org/10.1038/24036
Wahome PG, Cowan AE, Setlow B, Setlow P (2009) Levels and localization of mechanosensitive channel proteins in Bacillus subtilis. Arch Microbiol 191(5):403–414. https://doi.org/10.1007/s00203-009-0465-z
Wang G, Chen H, Xia Y, Cui J, Gu Z, Song Y, Chen YQ, Zhang H, Chen W (2013a) How are the non-classically secreted bacterial proteins released into the extracellular milieu? Curr Microbiol 67(6):688–695. https://doi.org/10.1007/s00284-013-0422-6
Wang G, Chen H, Zhang H, Song Y, Chen W (2013b) The secretion of an intrinsically disordered protein with different secretion signals in Bacillus subtilis. Curr Microbiol 66(6):566–572. https://doi.org/10.1007/s00284-013-0315-8
Wang G, Xia Y, Gu Z, Zhang H, Chen YQ, Chen H, Ai L, Chen W (2015) A new potential secretion pathway for recombinant proteins in Bacillus subtilis. Microb Cell Factories 14:179. https://doi.org/10.1186/s12934-015-0374-6
Wang G, Xia Y, Song X, Ai L (2016) Common non-classically secreted bacterial proteins with experimental evidence. Curr Microbiol 72(1):102–111. https://doi.org/10.1007/s00284-015-0915-6
Wang M, Wu J, Wu D (2018) Cloning and expression of the sucrose phosphorylase gene in Bacillus subtilis and synthesis of kojibiose using the recombinant enzyme. Microb Cell Factories 17(1):23. https://doi.org/10.1186/s12934-017-0842-2
Wickner W, Driessen AJ, Hartl FU (1991) The enzymology of protein translocation across the Escherichia coli plasma membrane. Annu Rev Biochem 60:101–124. https://doi.org/10.1146/annurev.bi.60.070191.000533
Wild K, Bange G, Motiejunas D, Kribelbauer J, Hendricks A, Segnitz B, Wade RC, Sinning I (2016) Structural basis for conserved regulation and adaptation of the signal recognition particle targeting complex. J Mol Biol 428(14):2880–2897. https://doi.org/10.1016/j.jmb.2016.05.015
Yang CK, Ewis HE, Zhang X, Lu CD, Hu HJ, Pan Y, Abdelal AT, Tai PC (2011) Nonclassical protein secretion by Bacillus subtilis in the stationary phase is not due to cell lysis. J Bacteriol 193(20):5607–5615. https://doi.org/10.1128/JB.05897-11
Yang CK, Zhang XZ, Lu CD, Tai PC (2014) An internal hydrophobic helical domain of Bacillus subtilis enolase is essential but not sufficient as a non-cleavable signal for its secretion. Biochem Biophys Res Commun 446(4):901–905. https://doi.org/10.1016/j.bbrc.2014.03.032
Zhao D, Yuan S, Xiong B, Sun H, Ye L, Li J, Zhang X, Bi C (2016) Development of a fast and easy method for Escherichia coli genome editing with CRISPR/Cas9. Microb Cell Factories 15(1):205. https://doi.org/10.1186/s12934-016-0605-5
Zhao L, Chen J, Sun J, Zhang D (2017) Multimer recognition and secretion by the non-classical secretion pathway in Bacillus subtilis. Sci Rep 7:44023. https://doi.org/10.1038/srep44023
Acknowledgments
The authors wish to express their gratitude for the great support received from the funding agencies.
Availability of data and materials
This is a review article without original data.
Funding
This work was supported by the National Key R&D Program of China (2018YFA0900302, 2018YFD0901001), the National Natural Science Foundation of China (NSFC 31800086), the Tianjin Science Fund for Distinguished Young Scholars (17JCJQJC45300), and the Science and Technology Service Network (STS) Initiative of the Chinese Academy of Sciences (CAS) (KFJ-STS-ZDTP-065).
Author information
Authors and Affiliations
Contributions
QK and DZ conceived the review; QK and DZ wrote the manuscript.
Corresponding author
Ethics declarations
Ethics approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kang, Q., Zhang, D. Principle and potential applications of the non-classical protein secretory pathway in bacteria. Appl Microbiol Biotechnol 104, 953–965 (2020). https://doi.org/10.1007/s00253-019-10285-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00253-019-10285-4