1.E.19 The Clostridium difficile TcdE Holin (TcdE Holin) Family

Toxigenic strains of C. difficile produce two large toxins (TcdA and TcdB) encoded within a pathogenicity locus. tcdE, encoded between tcdA and tcdB, encodes a 166 aa protein which causes death to E. coli when expressed, and the structure of TcdE resembles holins. TcdE acts on the bacterial membrane. Since TcdA and TcdB lack signal peptides, they may be released via TcdE either prior to or subsequent to cell lysis. Other Clostridial species bear homologues of TcdE.  This family belongs to the Phage holin 4 superfamily. 

The transport reaction believed to be catalyzed by TcdE is:

Toxin (in) Toxin (out)



This family belongs to the Holin IV Superfamily .

 

References:

El Meouche, I. and J. Peltier. (2018). Toxin release mediated by the novel autolysin Cwp19 in. Microb Cell 5: 421-423.

Govind, R. and B. Dupuy. (2012). Secretion of Clostridium difficile toxins A and B requires the holin-like protein TcdE. PLoS Pathog 8: e1002727.

Govind, R., L. Fitzwater, and R. Nichols. (2015). Observations on the Role of TcdE Isoforms in Clostridium difficile Toxin Secretion. J. Bacteriol. 197: 2600-2609.

Jin, M., T. Ye, and X. Zhang. (2013). Roles of bacteriophage GVE2 endolysin in host lysis at high temperatures. Microbiology 159: 1597-1605.

Kong M. and Ryu S. (2015). Bacteriophage PBC1 and its endolysin as an antimicrobial agent against Bacillus cereus. Appl Environ Microbiol. 81(7):2274-83.

Mehner-Breitfeld, D., C. Rathmann, T. Riedel, I. Just, R. Gerhard, J. Overmann, and T. Brüser. (2018). Evidence for an Adaptation of a Phage-Derived Holin/Endolysin System to Toxin Transport in. Front Microbiol 9: 2446.

Sirigi Reddy, A.R., B.P. Girinathan, R. Zapotocny, and R. Govind. (2013). Identification and characterization of Clostridium sordellii toxin gene regulator. J. Bacteriol. 195: 4246-4254.

Takác, M., A. Witte, and U. Bläsi. (2005). Functional analysis of the lysis genes of Staphylococcus aureus phage P68 in Escherichia coli. Microbiology 151: 2331-2342.

Tan, K.S., B.Y. Wee, and K.P. Song. (2001). Evidence for holin function of tcdE gene in the pathogenicity of Clostridium difficile. J. Med. Microbiol. 50: 613-619.

Zimmer, M., N. Vukov, S. Scherer, and M.J. Loessner. (2002). The murein hydrolase of the bacteriophage phi3626 dual lysis system is active against all tested Clostridium perfringens strains. Appl. Environ. Microbiol. 68: 5311-5317.

Examples:

TC#NameOrganismal TypeExample
1.E.19.1.1

Holin (161 aas)

Actinobacteria

Holin of Mobiluncus mulieris

 
1.E.19.1.10

Phage-related holin of 142 aas and 4 TMSs

Tenericutes

Holin of Acholeplasma laidlawii

 
1.E.19.1.11

Holin of 141 aas and 2 TMSs

Chloroflexi

Holin of Dehalococcoides ethenogenes

 
1.E.19.1.12

Holin of 137 aas and 2 TMSs (Jin et al. 2013).

Firmicutes

Holin of Geobacillus phage GBSV1

 
1.E.19.1.13

Toxin secretion/holin system; holin of 124 aas

Tenericutes

Holin of Mycoplasma sp.

 
1.E.19.1.14

Putative holin of 142 aas

Chloroflexi

Putative holin of Herpetosiphon aurantiacus

 
1.E.19.1.15

Putative holin of 141 aas and 3 TMSs

Bacteroidetes

Putative holin of Alistipes shahii

 
1.E.19.1.16

Holin of 138 aas and 3 TMSs (Kong and Ryu 2015).

Firmicute phage

Holin of Bacillus phage PBC1

 
1.E.19.1.17

Holin of 139 aas and 2 TMSs.

Holin of Bacteroides fragilis

 
1.E.19.1.18

Holin of a tactivirus of 131 aas and 3 TMSs.

Holin of Tectiviridae sp.

 
1.E.19.1.2

Uncharacterized protein

Firmicutes

Uncharacterized protein of Lachnospiraceae bacterium

 
1.E.19.1.3

Putative holin of 152 aas and 3 TMSs

Firmicutes

Putative holin of Brevibacillus brevis

 
1.E.19.1.4

Uncharacterized protein

Firmicute viruses

Uncharacterized protein of Bacillus phage IEBH

 
1.E.19.1.5

Uncharacterized protein (142 aas)

Firmicutes

Uncharacterized protein of Clostridium bolteae

 
1.E.19.1.6

Holin

Actinobacteria

Holin of Corynebacterium diphtheriae

 
1.E.19.1.7

Putative holin of 139 aas nd 3 TMSs

Thermatogae

Putative holin of Petrotoga mobilis

 
1.E.19.1.8

Prophage lambda Sa04 protein

Firmicutes

Sa04 protein of Megasphaera elsdenii

 
1.E.19.1.9

Holin (129 aas)

Fusobacteria

Fusobacterium sp. ZP-0

 
Examples:

TC#NameOrganismal TypeExample
1.E.19.2.1

Holin of 170 aas and 3 TMSs

Firmicutes

Holin of Macrococcus caseolyticus

 
1.E.19.2.2

Staphylococcus aureus phage P68 holin, hol15 (Takác et al. 2005).

Firmicute viruses

Hol15 of Staphylococcal phage P68

 
1.E.19.2.3

phage-like holin, YqxH1 (135 aas)

Firmicutes

YqxH1 of Bacillus amyloliquefaciens

 
Examples:

TC#NameOrganismal TypeExample
1.E.19.3.1

The C. difficile holin, TcdE.  TcdE acts as a holin-like protein to facilitate the release of C. difficile toxins A and B to the extracellular environment, but, unlike most phage holins, it does not cause the non-specific release of cytosolic contents. TcdE is thus a bacterial holin that releases toxins into the environment by a phage-like system (Tan et al. 2001; Govind and Dupuy 2012).  Different isoforms have differing activities in toxin release (Govind et al. 2015). An autolysin, Cwp19 (L7PGA3), may also play a role in toxin release (El Meouche and Peltier 2018). Adaptation of this phage-derived holin/endolysin system to toxin transport has been discussed (Mehner-Breitfeld et al. 2018). Thus, TcdE exists as three isoforms, differing with respect to their N-terminal extensions.  The longest TcdE isoform has a moderate effect on cell growth, whereas the shortest isoform strongly induces lysis. The effect of the longest isoform was inhibitory for cell lysis, implying a regulatory function of the N-terminal 24 residues.  Mehner-Breitfeld et al. 2018 analyzed the PaLoc sequence of 44 C. difficile isolates and found that four of these encode only the short TcdE isoform, and the most closely related holins from C. difficile phages only possess one of these initiation codons, indicating that the N-terminal extensions of TcdE evolved in C. difficile.

Firmicutes

TcdE of Clostridium difficile

 
1.E.19.3.2

Holin of 141 aas and 3 TMSs, TcsE (Sirigi Reddy et al. 2013).

Firmicutes

TcsE of Clostridium sordellii

 
Examples:

TC#NameOrganismal TypeExample
1.E.19.4.1

Holin of Clostridium phage phi3626.  The function has been demonstrated (Zimmer et al. 2002).  The charge distribution of this 2 TMS protein suggestions that the β-turn between TMSs 1 and 2, with 7 lys and arg residues, is in the cytoplasm and the N- and C-termini are in the periplasm (Zimmer et al. 2002).

Firmicute viruses

Holin of Clostridium phage phi3626

 
1.E.19.4.2

Toxin secretion holin of 137 aas and 3 TMSs.

Actinobacteria

Holin of Atopobium minutum

 
1.E.19.4.3

Putative holin of 158 aas and 3 TMSs.

Actinobacteria

Putative holin of Gardnerella vaginalis

 
1.E.19.4.4

Uncharacterized holin of 161 aas and 4 TMSs.

Putative holin of Candidatus Bathyarchaeota archaeon

 
1.E.19.4.5

Phage holin family protein of 146 aas and 3 TM

Holin of Methanoculleus sp.

 
Examples:

TC#NameOrganismal TypeExample
1.E.19.5.1

Holin of 162 aas and 3 TMSs

δ-proteobacteria

Putative holin of Desulfovibrio vulgaris

 
1.E.19.5.2

Holin of 199 aas and 3 TMSs.

Holin of Maridesulfovibrio frigidus

 
1.E.19.5.3

Phage holin family protein of 166 aas and 3 TMSs. 

 

Holin of Bilophila wadsworthia

 
Examples:

TC#NameOrganismal TypeExample
1.E.19.6.1

Putative holin of 178 aas and 4 TMSs

Bacteroidetes

Holin of Pedobacter saltans

 
1.E.19.6.2

Putative holin of 181 aas and 3 TMSs

Bacteroidetes

Holin of Capnocytophaga sputigena

 
1.E.19.6.3

Putative holin of 170 aas and 3 TMSs

Bacteroidetes

Holin of Cyclobacterium marinum (Flectobacillus marinus)