![]() It is suggested but not known yet whether Gram-negative bacteria use holins also for the transport of other proteins. In this review, all classes of mureinolytic enzymes that are transported by holins and therefore are closely related to phage holin/endolysin systems are termed “endolysin”. Gram-negative bacteria are shown to use prophage-derived non-lytic holin/endolysin systems to locally permeabilize the cell wall for the secretion of proteins (termed type 10 secretion, ). This view changed within the last decade, as holins have been identified in Gram-negative and Gram-positive bacteria that are involved in a non-lytic transport of folded proteins that in principle could also be transported by the Tat pathway. As such large lesions would not enable any specific transport but rather a non-specific release of cytoplasmic proteins, there have been doubts whether holins can be regarded as protein transport systems at all. Canonical holins were named “holins” when they were proposed to form membrane lesions, and well-studied holins of Gram-negative bacteria have indeed been shown to generate the expected large lesions of the cytoplasmic membrane. Accordingly, holins that are harnessed by bacteria to transport specific proteins are canonical holins. There are seven large holin superfamilies known, as listed in the Transporter Classification Database, but in principle holins are divided in two classes: (1) canonical holins that transport endolysins directly, and (2) pinholins that can depolarize the cytoplasmic membrane, which results in a release of endolysins that are membrane-anchored by so-called signal anchor release (SAR) domains. Holins originate from phages where they serve to release endolysins to the cell wall, resulting in peptidoglycan degradation and cell lysis. In several cases, such proteins are substrates of holin systems. Some extracytoplasmic proteins are neither transported by the general Sec or Tat pathways, nor by the recognized specific secretion pathways. In monoderm bacteria, transport across the cytoplasmic membrane can already release a protein into the environment, if only the passage through the cell wall is enabled. In diderm bacteria, proteins that are secreted into the environment need to cross the cytoplasmic and the outer membrane, and this transport can occur either in two steps, employing Sec or Tat systems for the cytoplasmic membrane and other pathways for the outer membrane, or it can occur in a single step by secretion systems that cross both membranes. Proteins that are transported by these systems are synthesized with N-terminal signal peptides that are important for the recognition by the transport systems and for the translocation mechanism. There are two general protein translocation pathways in the cytoplasmic membrane of bacteria: (1) The general secretion (Sec) system for the transport unfolded proteins, and (2) the twin-arginine translocation (Tat) system for the transport of folded proteins. NON-LYTIC HOLIN-MEDIATED TRANSPORT OF FOLDED PROTEINS–AN ALTERNATIVE TO THE Tat PATHWAY This model is strongly supported by a so far not recognized naturally occurring holin-endolysin fusion protein. Here we review the known cases of non-lytic holin-mediated transport and then focus on the structural and functional comparison of TatA and TpeE, resulting in a mechanistic model for holin-mediated transport. TpeE contains only one short transmembrane helix that is followed by an amphipathic helix, which is reminiscent of TatA, the membrane-permeabilizing component of the Tat translocon for folded proteins. The mechanism for non-lytic holin-mediated transport is unknown, but the recent finding that the small holin TpeE mediates a non-lytic toxin secretion in Clostridium perfringens opened new perspectives. ![]() In addition, clostridia, which do not possess the Tat pathway for transport of folded proteins, most likely employ non-lytic holin-mediated transport also for secretion of toxins and bacteriocins that are incompatible with the general Sec pathway. Phage-derived holins can be used for a non-lytic endolysin translocation to permeabilize the cell wall for the passage of secreted proteins. However, there are more and more examples known for non-lytic holin-dependent secretion of proteins by bacteria, indicating that holins somehow can transport proteins without causing large membrane lesions. Holins are generally believed to generate large membrane lesions that permit the passage of endolysins across the cytoplasmic membrane of prokaryotes, ultimately resulting in cell wall degradation and cell lysis.
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