Holins

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Background

Holin in the holin-endolysin system is a phage-encoded hydrophobic membrane protein involved in the substantial permeability of the cytoplasmic membrane, allowing the transfer of endotoxin to the periplasm and the attack of peptidoglycan. Holins act as protein clocks of the phage replication cycle that direct the endolysins to gain easy access close to the cell wall from within. Finally, the bacterial cells lose their stiffness, which eventually leads to cell lysis and death. These endolysins if applied externally to the target bacterium can easily have direct access to the cell wall causing rapid lysis of the bacterial cells. In elongated cells, the effective local concentrations required to form holin aggregates cannot be reached at the appropriate times to trigger lysis. This results in a delay in the lysis of bacterial cells and therefore an increase in the number of phages within them. For phage λ, interruptions in the cytoplasmic membrane by holins occur from the formation of "holes" ranging in size up to >1mm. Holins alone are unable to cause cell lysis since the destruction of the peptidoglycan is necessary to destabilize the cell wall. Of these 105 identified holin genes, the majority are from bacteriophages or prophages; some are from cryptic prophages.

Functions

Holins are encoded in phage genomes and promote cell lysis to release virions, and in bacterial genomes, they serve a variety of potential or established functions. This includes (i) the release of gene transfer agents, (ii) the promotion of differentiation programs such as those that allow sporulation and spore germination, (iii) the promotion of biofilm formation, (iv) the promotion of responses to stress conditions, and (v) the release of toxins and other proteins. Holins play two well-defined roles in the phage infection cycle. They allow the release of the endolysin, their primary function (e.g., their membrane permeation function), and they determine the timing of the end of the infection cycle, their secondary function, a "clock" function. Holins have recently been used in work attempting to construct potential vaccines.

Mechanism of Action (MoA)

A typical phage-encoded holin may accumulate harmlessly in the cytoplasmic membrane until triggered at a specific time to form huge pores, allowing an endolysin to reach the periplasm to degrade the peptidoglycan cell wall. Holins form pores in the cytoplasmic membrane of bacteria with the main purpose of releasing endotoxins, hydrolyzing the cell wall, and inducing cell death.

Fig.1 Transport of the endolysin mediated by holin or the TMD, which can result in different morphological changes of the host cells.¹

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Reference:

1. Wu, Zhifeng, et al. "The holin-endolysin lysis system of the OP2-Like phage X2 infecting Xanthomonas oryzae pv. oryzae." Viruses 13.10 (2021): 1949. Under Open Access license CC BY 4.0, without modification.