Heterogeneous Family of Cyclomodulins: Smart Weapons That Allow Bacteria to Hijack the Eukaryotic Cell Cycle and Promote Infections

Abstract

Some bacterial pathogens modulate signaling pathways of eukaryotic cells in order to subvert the host response for their own benefit, leading to successful colonization and invasion. Pathogenic bacteria produce multiple compounds that generate favorable conditions to their survival and growth during infection in eukaryotic hosts. Many bacterial toxins can alter the cell cycle progression of host cells, impairing essential cellular functions and impeding host cell division. This review summarizes current knowledge regarding cyclomodulins, a heterogeneous family of bacterial effectors that induce eukaryotic cell cycle alterations. We discuss the mechanisms of actions of cyclomodulins according to their biochemical properties, providing examples of various cyclomodulins such as cycle inhibiting factor, γ-glutamyltranspeptidase, cytolethal distending toxins, shiga toxin, subtilase toxin, anthrax toxin, cholera toxin, adenylate cyclase toxins, vacuolating cytotoxin, cytotoxic necrotizing factor, Panton-Valentine leukocidin, phenol soluble modulins, and mycolactone. Special attention is paid to the benefit provided by cyclomodulins to bacteria during colonization of the host.

Keywords: bacterial toxins; colonization; cyclomodulins; eukaryotic cell cycle alteration; infective efficiency; invasion; reduced host response.

Figure 1

Schematic presentation of the eukaryotic cell cycle and its regulation. The eukaryotic cell cycle consists of two gap phases, the G1 and the G2 phase, the S-phase, and the M (mitosis) phase. Cells can also enter a quiescent state, the G0 phase. Cell cycle phases are indicated by colored arrows. The cell cycle is regulated by complexes that are composed of cyclins, which are bound to cyclin-dependent protein kinases (CDKs). Cyclin-CDK complexes are positioned in the front of the arrow that designates the corresponding cell cycle phase. Cyclin-CDK complexes are controlled via checkpoint pathways whose role is to prevent the cell from progressing to the next stage when it is not allowed. Multiple stimuli that exert the checkpoint control are indicated in an appropriate text insert.

Figure 2

Signaling pathways of Shiga toxin (Stx), Cytolethal Distending Toxin (CDT) and Subtilase AB (SubAB). Activated and inactivated proteins are colored in green and red, respectively. Arrow colors match catalytic moieties of toxins. Dashed arrows are drawn when the precise mechanism is unknown. (i) Shiga toxin (Stx) binds to the cell-surface receptor Gb3 through the pentameric B subunit (dark red), followed by an internalization of the enzymatic A subunit (purple). Stx induces irreversible DNA damage that activates ATF3 and GADDs proteins, leading to cell cycle arrest in the G2 phase. Stx also induces CdkN3 that results in cell cycle arrest in the G2 phase. (ii) Cytolethal Distending Toxin (CDT) binds to an unknown cell membrane receptor through CdtA and CdtC (blue), leading to an enzymatic CdtB (yellow) internalization. CDT causes DNA damage that leads to the activation of ATM, followed by Cdc25C sequestration by CHK2. Consequently, Cdc25C is not free to bind CDK1, leading to its inhibition and, ultimately, to arrest of cells in the G2 phase. DNA damage caused by CDT also activates p53 and p21^Cip1, causing CDK2, and CycE inactivation and cell cycle arrest in the G1 phase. (iii) Subtilase AB binds integrins at the cell surface with the pentameric B subunit (orange) followed by the entrance of the enzymatic A subunit (pink). SubAB cleaves the chaperone BiP that activates PERK and eIF2α, leading to a translation inhibition. Finally, cyclin D1 is down-regulated and causes the arrest of cells in the G1 phase.

Figure 3

Signaling pathways of Anthrax toxin, Cholera toxin (CT) and Adenylate cyclase toxin (ACT) resulting in G1 phase arrest of the eukaryotic cell cycle. Activated and inactivated proteins are colored in green and red, respectively. Arrow colors match catalytic moieties of toxins. Dashed arrows are drawn when the precise mechanism is unknown. (i) Anthrax toxin is formed by EF, LF, and PA. Heptameric PA (gray) binds to either ANTXR1, ANTXR2, or ATR at the cell membrane and leads to the entrance of EF and LF into the cell. EF (green) induces cAMP production followed by inactivation of the c-Raf/MEK/ERK cascade, leading to Cyclin D1 inactivation. A cAMP increase induces PKA and CREB, leading to cyclin D1 inactivation. The level of p27^Kip1 is increased by cAMP and leads to cyclin D and, especially, Cyclin D1 inactivation. LF (dark green) directly inactivates MEK, leading to ERK and Cyclin D1 inactivation. (ii) Cholera toxin (CTX) binds to either GM1 or CEACAM5 at the cell membrane through the pentameric CTB subunit (black), leading to endocytosis of the catalytic CTA subunit (blue). CTX activates the G protein and leads to cAMP production followed by up-regulation of p27^Kip1 and p21^Cip1 and inactivation of the c-Raf/MEK/ERK cascade, leading to Cyclin D1, CDK4, and CDK6 inactivation. (iii) Adenylate cyclase toxin (ACT) binds to an unknown receptor at the cell surface through the pentameric subunit (purple), and the catalytic subunit (brown) is translocated to the cytosol. In the same way as EF, ACT induces production of cAMP that leads to inactivation of the c-Raf/MEK/ERK cascade, activation of PKA and CREB, activation of p27^Kip1 and, finally, inactivation of Cyclin D1. Inactivation of Cyclin D1, CDK4, and CDK6 leads to cell cycle arrest in the G1 phase.

Figure 4

Bacterial cyclomodulins alter the eukaryotic cell cycle for their own benefit. The names of bacteria and the abbreviations of cyclomodulins produced by those bacteria are indicated in red. Cell cycle phases are indicated by colored arrows. Zigzag red lines are attached to the phase in which the cell cycle is blocked by the corresponding cyclomodulin. The phases in which the cell cycle is blocked are indicated in an appropriate text insert. Black arrows display the biological effects related to the cyclomodulin-induced cell cycle arrest.