Biopolym. Cell. 2020; 36(6):409-422.
Protein aggregates carry non-genetic memory in bacteria after stresses
1Kukharenko O. Ye., 1, 2Terzova V. O., 1Zubova G. V.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03143
  2. National University of "Kyiv-Mohyla Academy"
    2, Skovorody Str., Kyiv, Ukraine, 04655


Protein aggregation is related to the formation of oligomers and aggregates, leading to impaired cellular processes. The protein aggregates formation is associated with pathologies and ageing in eukaryotes wherea in bacteria aggregation causes dramatic changes in growth rate, stress resistance and virulence, and eventually these aggregates play a functional role. Both cellular and environmental factors enhance protein damage via aggregation, nonetheless, upon sublethal doses of proteotoxic environmental stressors, protein aggregates may improve cellular robustness and carry a type of non-genetic memory of the previous stressors through several generations. Emerging data on aggregated proteins, carrying non-genetic (epigenetic) traits, show that protein-based inheritance is known within all three kingdoms of living organisms. This review focuses on the protein aggregates as carriers of non-genetic memory in bacteria.
Keywords: bacteria, protein aggregates, stress, epigenetics


[1] Danchin E, Wagner RH. Inclusive heritability: combining genetic and nongenetic information to study animal behavior and culture. Oikos.2010; 119(2):210-18.
[2] Holliday R, Pugh JE. DNA modification mechanisms and gene activity during development. Science. 1975;187(4173):226-32.
[3] Nanney DL. Epigenetic control systems. Proc Natl Acad Sci U S A. 1958;44(7):712-7.
[4] Riggs AD. X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet. 1975;14(1):9-25.
[5] Duempelmann L, Skribbe M, Bühler M. Small RNAs in the Transgenerational Inheritance of Epigenetic Information. Trends Genet. 2020;36(3):203-214.
[6] Harvey ZH, Chakravarty AK, Futia RA, Jarosz DF. A Prion Epigenetic Switch Establishes an Active Chromatin State. Cell. 2020;180(5):928-940.e14.
[7] Lindquist S. Lamarck redux: prions, Hsp90, and the inheritance of environmentally acquired traits. In: Molecular Frontiers Symposium 2011: Origin of Life and Molecular Evolution. 24 May 2011.
[8] Hammond CM, Strømme CB, Huang H, Patel DJ, Groth A. Histone chaperone networks shaping chromatin function. Nat Rev Mol Cell Biol. 2017;18(3):141-158.
[9] Harvey ZH, Chen Y, Jarosz DF. Protein-Based Inheritance: Epigenetics beyond the Chromosome. Mol Cell. 2018;69(2):195-202.
[10] Yuan AH, Hochschild A. A bacterial global regulator forms a prion. Science. 2017;355(6321):198-201.
[11] Fleming E, Yuan AH, Heller DM, Hochschild A. A bacteria-based genetic assay detects prion formation. Proc Natl Acad Sci U S A. 2019;116(10):4605-4610.
[12] Harrison PM. Evolutionary behaviour of bacterial prion-like proteins. PLoS One. 2019;14(3):e0213030.
[13] Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013;501(7465):45-51.
[14] Ageorges V, Monteiro R, Leroy S, Burgess CM, Pizza M, Chaucheyras-Durand F, Desvaux M. Molecular determinants of surface colonisation in diarrhoeagenic Escherichia coli (DEC): from bacterial adhesion to biofilm formation. FEMS Microbiol Rev. 2020;44(3):314-350.
[15] Wang W, Roberts CJ. Protein aggregation - Mechanisms, detection, and control. Int J Pharm. 2018;550(1-2):251-268.
[16] Tyedmers J, Mogk A, Bukau B. Cellular strategies for controlling protein aggregation. Nat Rev Mol Cell Biol. 2010;11(11):777-88.
[17] Cox D, Raeburn C, Sui X, Hatters DM. Protein aggregation in cell biology: An aggregomics perspective of health and disease. Semin Cell Dev Biol. 2020;99:40-54.
[18] Bednarska NG, Schymkowitz J, Rousseau F, Van Eldere J. Protein aggregation in bacteria: the thin boundary between functionality and toxicity. Microbiology (Reading). 2013;159(Pt 9):1795-1806.
[19] Schramm FD, Schroeder K, Jonas K. Protein aggregation in bacteria. FEMS Microbiol Rev. 2020;44(1):54-72.
[20] Revilla-García A, Fernández C, Moreno-Del Álamo M, de Los Ríos V, Vorberg IM, Giraldo R. Intercellular Transmission of a Synthetic Bacterial Cytotoxic Prion-Like Protein in Mammalian Cells. mBio. 2020;11(2):e02937-19.
[21] Alexandrov AI, Polyanskaya AB, Serpionov GV, Ter-Avanesyan MD, Kushnirov VV. The effects of amino acid composition of glutamine-rich domains on amyloid formation and fragmentation. PLoS One. 2012;7(10):e46458.
[22] Marcoleta A, Wien F, ArluisonV, Lagos R, Giraldo R. Bacterial Amyloids. eLS. John Wiley & Sons Ltd: Chichester, 2019.
[23] Narhi LO, Schmit J, Bechtold-Peters K, Sharma D. Classification of protein aggregates. J Pharm Sci. 2012;101(2):493-8.
[24] Weids AJ, Ibstedt S, Tamás MJ, Grant CM. Distinct stress conditions result in aggregation of proteins with similar properties. Sci Rep. 2016;6:24554.
[25] Shanmugam N, Baker MODG, Ball SR, Steain M, Pham CLL, Sunde M. Microbial functional amyloids serve diverse purposes for structure, adhesion and defence. Biophys Rev. 2019;11(3):287-302.
[26] Bowden GA, Paredes AM, Georgiou G. Structure and morphology of protein inclusion bodies in Escherichia coli. Biotechnology (N Y). 1991;9(8):725-30.
[27] Chapman MR, Robinson LS, Pinkner JS, Roth R, Heuser J, Hammar M, Normark S, Hultgren SJ. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science. 2002;295(5556):851-5.
[28] Schramm FD, Schroeder K, Alvelid J, Testa I, Jonas K. Growth-driven displacement of protein aggregates along the cell length ensures partitioning to both daughter cells in Caulobacter crescentus. Mol Microbiol. 2019;111(6):1430-1448.
[29] Govers SK, Mortier J, Adam A, Aertsen A. Protein aggregates encode epigenetic memory of stressful encounters in individual Escherichia coli cells. PLoS Biol. 2018;16(8):e2003853.
[30] Gupta A, Lloyd-Price J, Neeli-Venkata R, Oliveira SM, Ribeiro AS. In vivo kinetics of segregation and polar retention of MS2-GFP-RNA complexes in Escherichia coli. Biophys J. 2014;106(9):1928-37.
[31] Lindner AB, Madden R, Demarez A, Stewart EJ, Taddei F. Asymmetric segregation of protein aggregates is associated with cellular aging and rejuvenation. Proc Natl Acad Sci U S A. 2008;105(8):3076-81.
[32] Schramm DF. Stress response regulation and protein aggregate inheritance in Caulobacter crescentus. Stockholm: "Vivi Täckholmsalenpress", 2019; 81 p.
[33] Vedel S, Nunns H, Košmrlj A, Semsey S, Trusina A. Asymmetric damage segregation constitutes an emergent population-level stress response. Cell Syst. 2016;3(2):187-198.
[34] Wang X, Cole CG, DuPai CD, Davies BW. Protein Aggregation is Associated with Acinetobacter baumannii Desiccation Tolerance. Microorganisms. 2020;8(3):343.
[35] Govers SK, Aertsen A. Impact of high hydrostatic pressure processing on individual cellular resuscitation times and protein aggregates in Escherichia coli. Int J Food Microbiol. 2015;213:17-23.
[36] Gayán E, Govers SK, Aertsen A. Impact of high hydrostatic pressure on bacterial proteostasis. Biophys Chem. 2017;231:3-9.
[37] Hartl FU, Hayer-Hartl M. Converging concepts of protein folding in vitro and in vivo. Nat Struct Mol Biol. 2009;16(6):574-81.
[38] Borgqvist J, Welkenhuysen N, Cvijovic M. Synergistic effects of repair, resilience and retention of damage determine the conditions for replicative ageing. Sci Rep. 2020;10(1):1556.
[39] Butterfield SM, Lashuel HA. Amyloidogenic protein-membrane interactions: mechanistic insight from model systems. Angew Chem Int Ed Engl. 2010;49(33):5628-54.
[40] Malishev R, Abbasi R, Jelinek R, Chai L. Bacterial Model Membranes Reshape Fibrillation of a Functional Amyloid Protein. Biochemistry. 2018;57(35):5230-5238.
[41] Fernández C, Núñez-Ramírez R, Jiménez M, Rivas G, Giraldo R. RepA-WH1, the agent of an amyloid proteinopathy in bacteria, builds oligomeric pores through lipid vesicles. Sci Rep. 2016;6:23144.
[42] Molina-García L, Moreno-Del Álamo M, Botias P, Martín-Moldes Z, Fernández M, Sánchez-Gorostiaga A, Alonso-Del Valle A, Nogales J, García-Cantalejo J, Giraldo R. Outlining Core Pathways of Amyloid Toxicity in Bacteria with the RepA-WH1 Prionoid. Front Microbiol. 2017;8:539.
[43] Cámara-Almirón J, Caro-Astorga J, de Vicente A, Romero D. Beyond the expected: the structural and functional diversity of bacterial amyloids. Crit Rev Microbiol. 2018;44(6):653-666.
[44] Rouse SL, Hawthorne WJ, Berry JL, Chorev DS, Ionescu SA, Lambert S, Stylianou F, Ewert W, Mackie U, Morgan RML, Otzen D, Herbst FA, Nielsen PH, Dueholm M, Bayley H, Robinson CV, Hare S, Matthews S. A new class of hybrid secretion system is employed in Pseudomonas amyloid biogenesis. Nat Commun. 2017;8(1):263.
[45] Van Gerven N, Klein RD, Hultgren SJ, Remaut H. Bacterial amyloid formation: structural insights into curli biogensis. Trends Microbiol. 2015;23(11):693-706.
[46] Wang Y, Pu J, An B, Lu TK, Zhong C. Emerging Paradigms for Synthetic Design of Functional Amyloids. J Mol Biol. 2018;430(20):3720-34.
[47] Barran-Berdon AL, Ocampo S, Haider M, Morales-Aparicio J, Ottenberg G, Kendall A, Yarmola E, Mishra S, Long JR, Hagen SJ, Stubbs G, Brady LJ. Enhanced purification coupled with biophysical analyses shows cross-β structure as a core building block for Streptococcus mutans functional amyloids. Sci Rep. 2020;10(1):5138.
[48] Cámara-Almirón J, Navarro Y, Díaz-Martínez L, Magno-Pérez-Bryan MC, Molina-Santiago C, Pearson JR, de Vicente A, Pérez-García A, Romero D. Dual functionality of the amyloid protein TasA in Bacillus physiology and fitness on the phylloplane. Nat Commun. 2020;11(1):1859.
[49] Taglialegna A, Navarro S, Ventura S, Garnett JA, Matthews S, Penades JR, Lasa I, Valle J. Staphylococcal Bap Proteins Build Amyloid Scaffold Biofilm Matrices in Response to Environmental Signals. PLoS Pathog. 2016;12(6):e1005711.
[50] Alteri CJ, Xicohténcatl-Cortes J, Hess S, Caballero-Olín G, Girón JA, Friedman RL. Mycobacterium tuberculosis produces pili during human infection. Proc Natl Acad Sci U S A. 2007;104(12):5145-50.
[51] Oh J, Kim JG, Jeon E, Yoo CH, Moon JS, Rhee S, Hwang I. Amyloidogenesis of type III-dependent harpins from plant pathogenic bacteria. J Biol Chem. 2007;282(18):13601-9.
[52] Sampson TR, Challis C, Jain N, Moiseyenko A, Ladinsky MS, Shastri GG, Thron T, Needham BD, Horvath I, Debelius JW, Janssen S, Knight R, Wittung-Stafshede P, Gradinaru V, Chapman M, Mazmanian SK. A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice. Elife. 2020;9:e53111.
[53] Friedland RP, McMillan JD, Kurlawala Z. What are the molecular mechanisms by which functional bacterial amyloids influence amyloid beta deposition and neuroinflammation in neurodegenerative disorders? Int J Mol Sci. 2020;21(5):1652.
[54] Mortier J, Tadesse W, Govers SK, Aertsen A. Stress-induced protein aggregates shape population heterogeneity in bacteria. Curr Genet. 2019;65(4):865-869.
[55] Iglesias V, de Groot NS, Ventura S. Computational analysis of candidate prion-like proteins in bacteria and their role. Front Microbiol. 2015;6:1123.
[56] Pallarès I, Ventura S. The transcription terminator rho: a first bacterial prion. Trends Microbiol. 2017;25(6):434-437.
[57] Shahnawaz M, Park KW, Mukherjee A, Diaz-Espinoza R, Soto C. Prion-like characteristics of the bacterial protein Microcin E492. Sci Rep. 2017;7:45720.
[58] Liebman SW, Chernoff YO. Prions in yeast. Genetics. 2012;191(4):1041-72.
[59] Scheckel C, Aguzzi A. Prions, prionoids and protein misfolding disorders. Nat Rev Genet. 2018;19(7):405-418.