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Preserved Antibacterial Activity of Ribosomal Protein S15

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Preserved Antibacterial Activity of Ribosomal Protein S15 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.959346; this version posted February 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 New Tricks for an old molecule: Preserved antibacterial activity of 2 ribosomal protein S15 during evolution 3 4 Baozhen Qua, Zengyu Maa, Lan Yaoa, Zhan Gaoa, Shicui Zhanga,b* 5 aLaboratory for Evolution & Development, Institute of Evolution & 6 Marine Biodiversity and Department of Marine Biology, Ocean 7 University of China, Qingdao 266003, China 8 bLaboratory for Marine Biology and Biotechnology, Pilot National 9 Laboratory for Marine Science and Technology (Qingdao), Qingdao 10 266003, China 11 12 *Correspondence author 13 Dr. Shicui Zhang 14 Room 312, Darwin Building, 5 Yushan Road, Ocean University of China, 15 Qingdao 266003, China 16 Tel.: +86 532 82032787 17 E-mail: [email protected] 18 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.959346; this version posted February 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 19 20 21 22 23 Abstract 24 Previous studies show that some ribosomal proteins possess antimicrobial 25 peptide (AMP) activity. However, information as such remains rather 26 fragmentary and limited. Here we demonstrated for the first time that 27 amphioxus RPS15, BjRPS15, was a previously uncharacterized AMP, 28 which was not only capable of identifying Gram-negative and -positive 29 bacteria via interaction with LPS and LTA but also capable of killing the 30 bacteria. We also showed that both the sequence and 3D structure of 31 RPS15 and its prokaryotic homologs were highly conserved, suggesting 32 its antibacterial activity is universal across widely separated taxa. 33 Actually this was supported by the facts that the residues positioned at 34 45-67 formed the core region for the antimicrobial activity of BjRPS15, 35 and its prokaryotic counterparts, including 36 Nitrospirae RPS1933-55, Aquificae RPS1933-55 and P. syringae RPS1950-72, 37 similarly displayed antibacterial activities. BjRPS15 functioned by both 38 interaction with bacterial membrane via LPS and LTA and membrane 39 depolarization as well as induction of intracellular ROS. Moreover, we bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.959346; this version posted February 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 40 showed that RPS15 existed extracellularly in amphioxus, shrimp, 41 zebrafish and mice, hinting it may play a critical role in systematic 42 immunity in different animals. In addition, we found that neither 43 BjRPS15 nor its truncated form BjRPS1545-67 were toxic to mammalian 44 cells, making them promising lead molecules for the design of novel 45 peptide antibiotics against bacteria. Collectively, these indicate that 46 RPS15 is a new member of AMP with ancient origin and high 47 conservation throughout evolution. 48 Author summary 49 Ribosomal protein, a component of ribonucleoprotein particles, is 50 traditionally known involved in protein synthesis in a cell. Here we 51 demonstrated for the first time that amphioxus ribosomal protein 15 was a 52 novel antibacterial protein, capable of recognizing Gram-negative and 53 -positive bacteria as well as killing them. It killed the bacteria by a 54 combined mode of action of disrupting bacterial membrane integrity and 55 inducing radical oxygen species production. We also showed that both 56 eukaryotic ribosomal protein 15 and its prokaryotic counterpart ribosomal 57 protein 19 possessed antibacterial activity, indicating that the antibacterial 58 property is universal for this family of molecules. Moreover, we found 59 that ribosomal protein 15 was present in the circulation system of various 60 animals including shrimp, amphioxus, zebrafish and mice, suggesting it bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.959346; this version posted February 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 61 may physiologically play a key role in systematic immunity. Altogether, 62 our study provides a new angle for understanding the biological function 63 of ribosomal proteins. 64 Introduction 65 The ribosome is an organelle within the cytoplasm of living cells that is 66 composed of proteins and ribosomal RNAs (rRNAs), serving as the 67 site for assembly of polypeptides encoded by messenger RNAs (mRNAs). 68 Ribosomes are found in both prokaryotic and eukaryotic cells. In both 69 types of cells, ribosomes are composed of two subunits, one large and one 70 small [1,2]. Each subunit has its own mix of proteins and rRNAs. The 71 small and large subunits of eukaryotes are called 40S and 60S, 72 respectively, while those of prokaryotes called 30S and 50S, separately. 73 Ribosomal protein S15 (RPS15) is a component of the 40S subunit of 74 eukaryotes, while its homolog in prokaryotes is S19 (RPS19) of the 30S 75 subunit [3]. 76 Ribosomal proteins, in addition to their conventional role in 77 ribosome assembly and protein translation, are shown involved in diverse 78 physiological and pathological processes, such as neurodegeneration in 79 Parkinson's disease, tumorigenesis, immune signaling and development 80 [1,4,5]. Intriguingly, ribosomal proteins also show antimicrobial activity. 81 Initially, the antimicrobial peptide (AMP) cecropin, first isolated from the bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.959346; this version posted February 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 82 moth Hyalophora cecropia [6-8], was mapped to the N-terminal region of 83 the 50S ribosomal protein L1 of the pathogen Helicobacter pylori [9,10]. 84 Recently, the 50S ribosomal proteins L27 and L30 of the lactic acid 85 bacterium Lactobacillus salivarius were shown to possess antimicrobial 86 activity against Streptococcus pyogenes, Streptococcus uberis and 87 Enterococcus faecium [11]. Furthermore, antibacterial activity was also 88 observed for the 60S ribosomal protein L29 isolated from the gill of 89 pacific oyster Crassostrea gigas [12] and the 40S ribosomal protein S30 90 isolated from the skin of rainbow trout Oncorhynchus mykiss [13]. It is 91 thus clear that some ribosomal proteins of the small and large subunits of 92 both prokaryotic and eukaryotic ribosomes can function as AMP. 93 However, our information regarding ribosomal protein AMPs is rather 94 fragmentary and limited. Moreover, little is known about the mode of 95 action of ribosomal protein AMPs. In this study, we identified RPS15 of 96 amphioxus (Branchiostoma japonicum), BjRPS15, as a novel member of 97 AMP, and demonstrated that BjRPS15 executed its antimicrobial activity 98 by both the interaction with bacterial membrane via LPS and LTA and 99 membrane depolarization as well as production of intracellular ROS. We 100 also showed that the emergence of antimicrobial activity of RPS15 could 101 be traced to its prokaryotic homolog RPS19. This is the first report 102 showing that RPS15 and its prokaryotic homolog RPS19 function as an 103 AMP, much enriching our understanding of the biological activities of bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.959346; this version posted February 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 104 ribosomal proteins. 105 Results 106 Sequence characteristics and genomic structure of BjRPS15 107 The open reading frame (ORF) of BjRPS15 (GenBank accession number: 108 XP_019635827) obtained was 444 bp long, which encoded a deduced 109 protein of 147 amino acids with a calculated molecular weight of about 110 16.96 kDa and an isoelectric point (pI) of 10.31 (Fig 1A). Analysis by 111 SignalP showed that the deduced protein had no signal peptide, and 112 analysis by SMART program revealed that the protein possessed a single 113 Ribosomal-S19 domain at the residues 45 to 130 (Fig 1A). Analysis by 114 Antimicrobial Peptide Calculator and Predictor at APD revealed that the 115 BjRPS15 had a total hydrophobic ratio of 36% and a net charge of +19, 116 suggesting that BjRPS15 is a putative AMP. Prediction by CAMP 117 showed that the amino acid residues 45-67 118 (RRFSRGLKRKHLALIKKLRKAKK, designated BjRPS1545-67) were 119 the core region of antimicrobial activity of BjRPS15 (Fig 1A). As shown 120 in Table 1, the peptide BjRPS1545-67 had a total hydrophobic ratio of 34% 121 and a net charge of +12.04. The 3D modeling revealed that BjRPS15 was 122 composed of 7 α-helice and 3 β-sheets (Fig 1B), and BjRPS1545-67 123 comprised 2 α-helice (Fig 1C). 124 Protein sequence comparison showed that BjRPS15 shared 75.2% to bioRxiv preprint doi: https://doi.org/10.1101/2020.02.21.959346; this version posted February 21, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
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