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1.E.14 The CidA/LrgA Holin (CidA/LrgA Holin) Family

See 1.E for a generalized description of holins.

CidA (TC# 1.E.14.1.2) and LrgA (TC# 1.E.14.1.1) of Staphylococcus aureus are homologous holin and anti-holin proteins, each with 4 putative TMSs (Ranjit et al. 2011). They are members of a large family of putative murine hydrolase exporters from a wide range of Gram-positive and Gram-negative bacteria as well as archaea. Most vary in size between 100 and 160 aas although a few are larger. It has been proposed that CidAB (23% and 32% identical to LrgAB, respectively) are involved in programmed cell death in a process that is analogous to apoptosis in eukaryotes (Bayles, 2003). They regulate and influence biofilm formation by releasing DNA from lysed cells which contributes to the biofilm matrix. CidA, a 131 aa protein with 4 putative TMSs, is believed to be the holin which exports the autolysin CidB, while LrgA may be an antiholin. If this is a general mechanism for programmed cell death, this would explain their near ubiquity in the prokaryotic world. The roles of CidA and LrgA as holins have been confirmed, but the lrgAB operon also facilitates pyruvate uptake during microaerobic and anaerobic growth (Laabei and Duggan 2022).

The cidABC operon is activated by CidR in the presence of acetic acid (Yang et al., 2005).  Both CidAB and LrgAB affect biofilm formation, oxidative stress, stationary phase survival and antibiotic tolerance in a reciprocal fashion, and their genes are regulated by the LytSR two component regulatory system (Sharma-Kuinkel et al. 2009).   Microfluidic techniques have been used to follow gene expression temporally and spatially during biofilm formation, revealing that both cidA and lrgA are expressed mostly in the interior of tower structures in the biofilms, regulated by oxygen availability (Moormeier et al. 2013).  Analogous proteins may be linked to competence in S. mutants (Ahn et al. 2012).  LytST induces ysbA transcription in the presence of pyruvate, and YsbA is involved in pyruvate utilization possibly by functioning as pyruvate uptake system (van den Esker et al. 2016).  This brings into question to functions of these proteins as holins and anti-holins.

References associated with 1.E.14 family:

Ahn, S.J., M.D. Qu, E. Roberts, R.A. Burne, and K.C. Rice. (2012). Identification of the Streptococcus mutans LytST two-component regulon reveals its contribution to oxidative stress tolerance. BMC Microbiol 12: 187. 22937869
Bayles, K.W. (2003). Are the molecular strategies that control apoptosis conserved in bacteria? Trends Microbiol. 11: 306-311. 12875813
Brunskill, E.W. and K.W. Bayles. (1996). Identification of LytSR-regulated genes from Staphylococcus aureus. J. Bacteriol. 178: 5810-5812. 8824633
Chen, Y., K. Gozzi, F. Yan, and Y. Chai. (2015). Acetic Acid Acts as a Volatile Signal To Stimulate Bacterial Biofilm Formation. MBio 6: e00392. 26060272
Desvaux, M., A. Khan, S.A. Beatson, A. Scott-Tucker, and I.R. Henderson. (2005). Protein secretion systems in Fusobacterium nucleatum: genomic identification of Type 4 piliation and complete Type V pathways brings new insight into mechanisms of pathogenesis. Biochim. Biophys. Acta. 1713: 92-112. 15993836
Endres, J.L., S.S. Chaudhari, X. Zhang, J. Prahlad, S.Q. Wang, L.A. Foley, S. Luca, J.L. Bose, V.C. Thomas, and K.W. Bayles. (2022). The Staphylococcus aureus CidA and LrgA Proteins Are Functional Holins Involved in the Transport of By-Products of Carbohydrate Metabolism. mBio e0282721. [Epub: Ahead of Print] 35100878
Fischer A., Kambara K., Meyer H., Stenz L., Bonetti EJ., Girard M., Lalk M., Francois P. and Schrenzel J. (2014). GdpS contributes to Staphylococcus aureus biofilm formation by regulation of eDNA release. Int J Med Microbiol. 304(3-4):284-99. 24275081
Laabei, M. and S. Duggan. (2022). CidA and LrgA: a "Hole" Lot More than Programmed Cell Death. mBio 13: e0076122. 35608302
Lee, J.H., Y.G. Kim, S. Yong Ryu, and J. Lee. (2016). Calcium-chelating alizarin and other anthraquinones inhibit biofilm formation and the hemolytic activity of Staphylococcus aureus. Sci Rep 6: 19267. 26763935
Moormeier, D.E., J.L. Endres, E.E. Mann, M.R. Sadykov, A.R. Horswill, K.C. Rice, P.D. Fey, and K.W. Bayles. (2013). Use of microfluidic technology to analyze gene expression during Staphylococcus aureus biofilm formation reveals distinct physiological niches. Appl. Environ. Microbiol. 79: 3413-3424. 23524683
Nguyen-Vo, T.P., S. Ko, H. Ryu, J.R. Kim, D. Kim, and S. Park. (2020). Systems evaluation reveals novel transporter YohJK renders 3-hydroxypropionate tolerance in Escherichia coli. Sci Rep 10: 19064. 33149261
Patton, T.G., K.C. Rice, M.K. Foster, and K.W. Bayles. (2005). The Staphylococcus aureus cidC gene encodes a pyruvate oxidase that affects acetate metabolism and cell death in stationary phase. Mol. Microbiol. 56: 1664-1674. 15916614
Ranjit, D.K., J.L. Endres, and K.W. Bayles. (2011). Staphylococcus aureus CidA and LrgA proteins exhibit holin-like properties. J. Bacteriol. 193: 2468-2476. 21421752
Sharma-Kuinkel, B.K., E.E. Mann, J.S. Ahn, L.J. Kuechenmeister, P.M. Dunman, and K.W. Bayles. (2009). The Staphylococcus aureus LytSR two-component regulatory system affects biofilm formation. J. Bacteriol. 191: 4767-4775. 19502411
van den Esker, M.H., &.#.1.9.3.;.T. Kovács, and O.P. Kuipers. (2016). YsbA and LytST are essential for pyruvate utilization in Bacillus subtilis. Environ Microbiol. [Epub: Ahead of Print] 27422364
Yang, S.J., K.C. Rice, R.J. Brown, T.G. Patton, L.E. Liou, Y.H. Park, and K.W. Bayles. (2005). A LysR-type regulator, CidR, is required for induction of the Staphylococcus aureus cidABC operon. J. Bacteriol. 187: 5893-5900. 16109930