The Variety in the Common Theme of Translation Inhibition by Type II Toxin-Antitoxin Systems

Abstract

Type II Toxin-antitoxin (TA) modules are bacterial operons that encode a toxic protein and its antidote, which form a self-regulating genetic system. Antitoxins put a halter on toxins in many ways that distinguish different types of TA modules. In type II TA modules, toxin and antitoxin are proteins that form a complex which physically sequesters the toxin, thereby preventing its toxic activity. Type II toxins inhibit various cellular processes, however, the translation process appears to be their favorite target and nearly every step of this complex process is inhibited by type II toxins. The structural features, enzymatic activities and target specificities of the different toxin families are discussed. Finally, this review emphasizes that the structural folds presented by these toxins are not restricted to type II TA toxins or to one particular cellular target, and discusses why so many of them evolved to target translation as well as the recent developments regarding the role(s) of these systems in bacterial physiology and evolution.

Keywords: mobile genetic elements; persistence; programmed cell death; toxins; translation.

FIGURE 1

Activities of type II TA toxins. Cellular targets of the toxins are depicted in black and white; toxins are depicted as red circles – open circles for toxins hydrolyzing chemical bonds, circles with diamond for toxins transferring chemical groups on the targets. Ac stands for acetylation, and P for phosphorylation.

FIGURE 2

MazF toxins and their specificity of RNA cleavage. MazF protein sequences were aligned and an average distance tree was build (BLOSUM 62, JalView) (Waterhouse et al., 2009). Substrate specificity is indicated (right). The cleavage position of the substrate is indicated by an arrow. Subsets of toxins sharing similar target sequences are boxed with different colors. Protein identifiers and cleavage specificity were taken from: E. coli MazF (ChpAK) (NP_417262.1) (Culviner and Laub, 2018; Mets et al., 2019), ChpBK (NP_418646.1) (Zhang et al., 2005), Kid (PemK) (YP_003937673.1) (Munoz-Gomez et al., 2004; Zhang et al., 2004); Bacillus subtilis MazF_bs (AOR96854.1) (Park et al., 2011); Bacillus anthracis MoxT (NP_842807.1) (Verma and Bhatnagar, 2014); Staphylococcus aureus MazF_sa (BBJ19047.1) (Zhu et al., 2009); Staphylococcus equorum MazF_seq (AFV93478.1) (Schuster et al., 2013); Clostridium difficile MazF_cd (YP_001089981.1) (Rothenbacher et al., 2012); Legionella pneumophila MazF_lp (CCD10720.1) (Shaku et al., 2018); Deinococcus radiodurans MazF_DR0417 (AAF09995.1) (Miyamoto et al., 2017); Haloquadratum walsbyi MazF_hw (WP_048066888.1) (Yamaguchi et al., 2012); Pseudomonas putida MazF_pp (NP_742932.1) (Miyamoto et al., 2016a); Myxococcus xanthus MazF_mx (SDX28280.1) (Nariya and Inouye, 2008); Methanohalobium evestigatum MazF_me (WP_013195679.1); Nitrosomonas europaea MazF_ne1 (WP_011111532.1) (Miyamoto et al., 2018), MazF_NE1181 (CAD85092.1) (Miyamoto et al., 2016b); Mycobacterium tuberculosis MazF-mt1 (NP_217317.1) (Zhu et al., 2006), MazF-mt3 (NP_216507.1) (Zhu et al., 2008; Schifano et al., 2014), MazF-mt6 (NP_215618.1) (Schifano et al., 2013), MazF-mt7 (NP_216011.1) (Zhu et al., 2008), MazF-mt9 (YP_004837055.2) (Barth et al., 2019).

FIGURE 3

Toxin structures. Structures of the toxins from different families representing different structural folds (noted in brackets) are shown. These domains are common in proteins of the defense and offense systems (HEPN, Cas2, BECR, FIC), RNA processing (dsRBD, PIN), eukaryotic cell signaling (SH3-barrel, (PI)3/4-kinase) or various other functions (GNAT). Structures are colored in rainbow from N-terminus (blue) to C-terminus (red), in cases of dimers the second monomer is in gray. Structures were visualized using ChimeraX, PDB codes were following: E. coli MazF:3nfc; E. coli HicAB:6hpb (Manav et al., 2019); S. oneidensis SO_3166-SO3165 (HEPN): 5yep (Jia et al., 2018); H. pylori HP0315 (VapD): 3ui3 (Kwon et al., 2012); S. flexneri VapC^D7A: 5ecw (Xu et al., 2016); E. coli RelE^{R81A, R83A}: 2kc9 (Li et al., 2009); E. coli HipA^S150A: 3tpb (Schumacher et al., 2012); E. coli AtaT^Y144F: 6gtp (Jurenas et al., 2019); prophage P1 Phd-Doc: 3k33 (Garcia-Pino et al., 2010). In the cases of structures in complexes with antitoxin, the coordinates of antitoxin were deleted.

FIGURE 4

VapC toxins and their specificity of RNA cleavage. VapC protein sequences were aligned and an average distance tree was build (BLOSUM 62, JalView) (Waterhouse et al., 2009). Substrate specificity is indicated (right). Toxin cleavage position is marked by an arrow, tRNA anticodon sequence is underlined, in the case of rRNA numbers of nucleotide positions are indicated in superscript. Additional targets and sequences are marked in the boxes on the right. Subsets of toxins sharing similar target sequences are boxed with different colors. Protein identifiers and cleavage specificity were taken from: Haemophilus influenzae VapC1_Hin (NP_438487.1), VapC2_Hin (NP_439108.1) (Walling and Butler, 2018); Salmonella enterica VapC_LT2 (NP_461950.1), Shigella flexneri MvpT (AMN61047.1) (Winther and Gerdes, 2011); Leptospira interrogans VapC_Lin (AAS71220.1) (Lopes et al., 2014); Mycobacterium tuberculosis VapC-mt4 (NP_215109.1) (Cruz et al., 2015; Winther et al., 2016), VapC-mt11 (NP_216077.1) (Winther et al., 2016; Cintron et al., 2019), VapC-mt15(NP_216526.1), VapC-mt25 (NP_214791.1), VapC-Mt28 (NP_215123.1), VapC-mt29 (NP_215131.1), VapC-mt30(NP_215138.1), VapC-mt32(NP_215630.1), VapC-mt33 (NP_215758.1), VapC-mt37 (NP_216619.1), VapC-mt39 (NP_217046.1) (Winther et al., 2016), VapC-mt20 (NP_217065.1), VapC-mt26 (NP_215096.1) (Winther et al., 2013, 2016), VapC-mt1 (NP_214579.1) (McKenzie et al., 2012; Sharrock et al., 2018), VapC-mt19 (NP_217064.1), VapC-mt27 (NP_215112.1) (Sharrock et al., 2018), Pyrobaculum aerophilum VapC_PAE2754 (WP_011008882.1), VapC_PAE0151 (WP_011007068.1) (McKenzie et al., 2012); Metallosphaera prunae VapC3_Mpr (WP_012020824.1), VapC7_Mpr (WP_012021162.1), VapC8_Mpr (WP_012021192.1) (Mukherjee et al., 2017).