Pathways
Molecular pathways
The cell-cycle circuit on the network page decides when things happen. These modules are the machinery it drives: they move the chromosome, choose where the cell divides, and build the flagellum, pili, stalk and holdfast. Step through each one, or select any part to see its evidence.
Chromosome segregation: ParABS, PopZ, TipN
After replication starts at the polar origin, the ParB-bound parS centromere beside the origin is moved to the opposite (new) pole by the ParA ATPase. TipN and PopZ keep transport directional, PopZ captures and anchors the arriving ori–ParB complex, and SMC loaded at parS aligns the chromosome arms.
The interactive diagram needs JavaScript; the parts and interactions are listed below.
Parts and interactions, with evidence
| From | Interaction | To | Note | Evidence |
|---|---|---|---|---|
| ParB | binds | parS | ParB binds DNA sequences adjacent to the origin (parS) | Mohl & Gober 1997; Toro et al. 2008 |
| ori (Cori) | precedes | Origin translocation | The 8-kb region holding ori and parS is what moves rapidly to the opposite pole | Toro et al. 2008 |
| Replication initiation | precedes | Origin translocation | On initiation the ori/parS region moves to the far pole; segregation waits until parS is replicated | Toro et al. 2008; Jensen & Shapiro 1999 |
| ParB | inhibits | ParA | ParB binds and destabilizes ParA structures; ParA retracts on contact with ParB | Ptacin et al. 2010; Shebelut et al. 2010 |
| ParA | activates | Origin translocation | ParA ATPase drives partition-complex transport; an ATPase mutant halts segregation | Toro et al. 2008; Ptacin et al. 2010; Lim et al. 2014 |
| TipN | binds | ParA | TipN interacts with ParA at the new pole, keeping transport directional | Schofield et al. 2010; Ptacin et al. 2010 |
| PopZ | binds | ParB | PopZ binds ParB directly and tethers the ori–ParB complex at the pole | Bowman et al. 2008; Ebersbach et al. 2008 |
| PopZ | recruits | ParA | Released ParA is recruited into the polar PopZ structure, enforcing pole-directed transport | Ptacin et al. 2014 |
| ParA | activates | PopZ | A local rise in ParA promotes PopZ matrix assembly at the new pole (unipolar to bipolar) | Laloux & Jacobs-Wagner 2013 |
| MreB | localizes / scaffolds | PopZ | Polar PopZ accumulation by diffusion/capture requires the MreB cytoskeleton | Bowman et al. 2008 |
| MreB | activates | Origin translocation | One replicated origin moves to the opposite end in an MreB-dependent manner | Thanbichler & Shapiro 2006 |
| ParB | recruits | SMC | SMC is recruited to parS and its arm-alignment activity depends on ParB | Tran et al. 2017 |
| SMC | activates | Ordered chromosome layout | SMC promotes colinearity of the chromosome arms; smc null cells mislocalize ori/ter | Le et al. 2013; Tran et al. 2017; Jensen & Shapiro 1999 |
| ZitP | localizes / scaffolds | PopZ | ZitP binds PopZ and regulates the localization of PopZ and ParB | Bergé et al. 2016 |
| ParB | recruits | MipZ | Hand-off: MipZ forms a complex with ParB near ori and moves with it to the poles | Thanbichler & Shapiro 2006 |
| Origin translocation | precedes | Ordered chromosome layout | Newly replicated loci follow the origin in chronological order to their final positions | Viollier et al. 2004 |
- ori (Cori) dna-site — Replication origin; sits at one cell pole and, once replicated, one copy moves rapidly to the opposite pole. Jensen & Shapiro 1999; Toro et al. 2008
- parS dna-site — Centromere-like site near ori bound by ParB; the site of segregation force, independent of its chromosomal position. Toro et al. 2008; Mohl & Gober 1997
- ParB protein — Centromere-binding protein at parS; destabilizes ParA structures and is anchored at the poles by PopZ. Mohl & Gober 1997; Ptacin et al. 2010; Bowman et al. 2008
- ParA protein — ATPase forming a nucleoid-bound structure; ParB-stimulated disassembly moves the partition complex. Ptacin et al. 2010; Toro et al. 2008; Lim et al. 2014; Shebelut et al. 2010
- PopZ protein — Self-assembling proline-rich polar matrix; anchors ori–ParB at the poles and sequesters released ParA. Bowman et al. 2008; Ebersbach et al. 2008; Ptacin et al. 2014; Laloux & Jacobs-Wagner 2013
- TipN protein — New-pole landmark; interacts with ParA at the new pole to keep partition-complex motion directional and fast. Lam et al. 2006; Schofield et al. 2010; Ptacin et al. 2010
- SMC protein — Structural maintenance of chromosomes protein; loaded at parS in a ParB-dependent way, aligns the two chromosome arms. Jensen & Shapiro 1999; Le et al. 2013; Tran et al. 2017
- ZitP protein — Bipolar zinc-finger protein that binds PopZ and regulates polar localization of ParB and PopZ and cytokinesis. Bergé et al. 2016
- MreB protein — Actin-like cytoskeleton; required for polar PopZ accumulation and for origin movement to the opposite pole. Bowman et al. 2008; Thanbichler & Shapiro 2006
- MipZ protein — Hand-off to division-site module: division inhibitor that binds ParB near ori and travels with it to the poles. Thanbichler & Shapiro 2006
- Replication initiation process — Hand-off from the core cell-cycle module (DnaA/CtrA); duplicates the ori/parS region and starts segregation. Toro et al. 2008
- Origin translocation process — Rapid, directed move of one ori/parS copy across the cell to the new pole; an ordered multistep process. Toro et al. 2008; Shebelut et al. 2010; Viollier et al. 2004
- Ordered chromosome layout process — Each locus has a subcellular address in linear order along the cell; loci are placed as they are replicated. Viollier et al. 2004; Le et al. 2013
Division-site selection and the divisome
MipZ, carried to both poles by ParB, forms bipolar gradients that block FtsZ polymerization near the poles, so the Z-ring assembles at midcell where MipZ is lowest. FtsZ then recruits FzlA, FzlC and later divisome proteins (FtsA, FtsN, FtsW/FtsI, DipM) that constrict and separate the envelope.
The interactive diagram needs JavaScript; the parts and interactions are listed below.
Parts and interactions, with evidence
| From | Interaction | To | Note | Evidence |
|---|---|---|---|---|
| ParB | recruits | MipZ | Polar ParB complexes bind MipZ and stimulate formation of ATP-bound MipZ dimers | Thanbichler & Shapiro 2006; Kiekebusch et al. 2012 |
| MipZ | binds | Nucleoid DNA | ATP-MipZ dimers bind chromosomal DNA near poles; ATP hydrolysis releases diffusible monomers | Kiekebusch et al. 2012 |
| MipZ | inhibits | FtsZ | MipZ blocks FtsZ polymerization: sequesters monomers and caps (+) ends of FtsZ polymers | Thanbichler & Shapiro 2006; Corrales-Guerrero et al. 2022 |
| FtsZ | precedes | Z-ring | FtsZ ring forms at midcell, the region of lowest MipZ concentration | Thanbichler & Shapiro 2006 |
| CtrA | represses transcription | FtsZ | CtrA binds a site overlapping the ftsZ start site and represses it in swarmer cells | Kelly et al. 1998 |
| KidO | inhibits | FtsZ | KidO acts directly on FtsZ to tune cytokinesis with the cell cycle | Radhakrishnan et al. 2010 |
| FzlA | binds | Z-ring | FzlA binds and curves FtsZ filaments; FzlA–FtsZ structures resist MipZ depolymerization | Goley et al. 2010; Lariviere et al. 2018 |
| FzlC | binds | Z-ring | FzlC binds membranes and recruits FtsZ to them via the FtsZ C-terminal peptide | Meier et al. 2016 |
| Z-ring | precedes | FtsA | FtsA arrives after Z-ring formation, early FtsZ-binders and PG-remodelling proteins | Goley et al. 2011; Meier et al. 2016 |
| FzlA | activates | FtsW / FtsI | FzlA links FtsZ to activation and spatial orientation of the septal synthases FtsW/FtsI | Lariviere et al. 2019 |
| FtsN | recruits | DipM | DipM is recruited to the constriction site through interaction with FtsN | Möll et al. 2010 |
| Z-ring | recruits | DipM | DipM localizes to the division site FtsZ-dependently via its PG-binding LysM domains | Goley et al. 2010; Poggio et al. 2010 |
| FtsW / FtsI | activates | Constriction & separation | Septal PG synthesis by FtsW/FtsI drives constriction; FzlA needed for proper rate | Lariviere et al. 2019 |
| DipM | activates | Constriction & separation | DipM remodels septal PG; without it outer-membrane invagination and separation are delayed | Möll et al. 2010; Goley et al. 2010 |
| Crescentin (CreS) | activates | Cell curvature | Crescentin filament creates a sidewall elongation-rate gradient that curves the cell | Ausmees et al. 2003; Cabeen et al. 2009 |
- ParB protein — Hand-off from chromosome-segregation module: centromere-binding protein at the polar ori regions; seeds MipZ dimers. Thanbichler & Shapiro 2006; Kiekebusch et al. 2012
- MipZ protein — P-loop ATPase; ParB-stimulated ATP dimers bind the nucleoid near poles, forming gradients that block FtsZ polymerization. Thanbichler & Shapiro 2006; Kiekebusch et al. 2012; Corrales-Guerrero et al. 2022
- FtsZ protein — Tubulin-like GTPase; cell-cycle transcription and proteolysis limit it to replicating cells; also guides midcell PG precursor synthesis. Kelly et al. 1998; Aaron et al. 2007
- FzlA protein — Essential FtsZ-binding protein; curves FtsZ filaments into helical bundles resistant to MipZ; sets constriction rate. Goley et al. 2010; Lariviere et al. 2018
- FzlC protein — Early FtsZ-binding membrane anchor that tethers FtsZ via its C-terminal peptide; linked to cell wall hydrolysis. Goley et al. 2010; Meier et al. 2016
- FtsA protein — FtsZ membrane tether that in Caulobacter reaches midcell after a stable Z-ring and early PG-remodelling proteins. Goley et al. 2011; Meier et al. 2016
- FtsW / FtsI protein — Septal PG synthases; hyperactive alleles make fzlA non-essential, so FzlA signals their activation. Lariviere et al. 2019
- FtsN protein — Late cell-division protein that recruits DipM to the constriction site. Möll et al. 2010
- DipM protein — LysM/LytM periplasmic PG-remodelling factor at the septum; needed for envelope invagination and outer-membrane constriction. Möll et al. 2010; Goley et al. 2010; Poggio et al. 2010
- KidO protein — NAD(H)-binding oxidoreductase homolog acting on FtsZ and stimulating DivJ; ClpXP-degraded at G1→S together with CtrA. Radhakrishnan et al. 2010
- CtrA protein — Hand-off from core module: binds the ftsZ promoter and represses ftsZ transcription in swarmer cells. Kelly et al. 1998
- Crescentin (CreS) protein — Intermediate filament-like protein along the inner curvature; required for vibrioid shape (null cells are straight rods). Ausmees et al. 2003; Cabeen et al. 2009
- Nucleoid DNA structure — Chromosomal DNA that retains ATP-bound MipZ dimers near the poles until ATP hydrolysis releases monomers. Kiekebusch et al. 2012
- Z-ring structure — FtsZ ring assembled at midcell, the MipZ minimum; scaffolds the divisome and directs septal PG insertion. Thanbichler & Shapiro 2006; Goley et al. 2011; Lariviere et al. 2018
- Constriction & separation process — Coordinated invagination of inner membrane, PG and outer membrane, then cell separation. Goley et al. 2011; Möll et al. 2010
- Cell curvature process — Crescent shape arising from an elongation-rate gradient across the sidewall imposed by the strained crescentin filament. Cabeen et al. 2009
Flagellar hierarchy, ejection and chemotaxis
Flagellar genes form a four-tier hierarchy: CtrA activates class II genes (MS ring, switch, export, FlbD), whose assembled products license FlbD/σ54-dependent class III and IV transcription, and hook completion licenses flagellin translation (FlaF vs FlbT). The flagellum is built at the TipN/TipF-marked new pole, ejected in a PleD-dependent way at the swarmer-to-stalked transition, and a CtrA-dependent chemotaxis operon builds a polar receptor array.
The interactive diagram needs JavaScript; the parts and interactions are listed below.
Parts and interactions, with evidence
| From | Interaction | To | Note | Evidence |
|---|---|---|---|---|
| CtrA | activates transcription | Class II genes | CtrA controls flagellar promoters; ChIP shows CtrA at the class II fliF promoter | Quon et al. 1996; Laub et al. 2002; Davis & Viollier 2011 |
| CtrA | activates transcription | Major che operon | The major chemotaxis operon requires CtrA but not RpoN or class II genes | Jones et al. 2001 |
| TipN | localizes / scaffolds | TipF | TipF relies on TipN for positioning at the new pole | Huitema et al. 2006 |
| TipF | recruits | Class II genes | Activated TipF recruits flagellar switch proteins and PflI at the TipN-marked pole | Davis et al. 2013 |
| Class II genes | precedes | Class III genes | Assembly of MS ring, switch and export apparatus is required for class III transcription | Mangan et al. 1999; Anderson & Newton 1997 |
| FliX | inhibits | FlbD | FliX binds FlbD and represses it when the class II structure is missing | Muir & Gober 2004 |
| FlbD | activates transcription | Class III genes | FlbD activates σ54 promoters of class III genes via ftr enhancer elements | Ramakrishnan & Newton 1990; Wu et al. 1995 |
| σ54 (RpoN) | activates transcription | Class III genes | σ54 is required for level III transcription and recognizes the flbG promoter | Anderson et al. 1995; Brun & Shapiro 1992 |
| FlbD | activates transcription | Class IV flagellins | FlbD also activates σ54-dependent class IV promoters, incl. flagellin operons | Ramakrishnan & Newton 1990; Wu et al. 1995 |
| Class III genes | precedes | Class IV flagellins | Basal body–hook completion is the checkpoint for flagellin translation | Anderson & Newton 1997; Llewellyn et al. 2005 |
| FlbT | represses | Class IV flagellins | FlbT binds the fljK 5' UTR, inhibiting translation and destabilizing the mRNA | Anderson & Gober 2000; Mangan et al. 1999 |
| FlaF | activates | Class IV flagellins | FlaF is required for fljK translation; FlbT and FlaF act in opposition | Llewellyn et al. 2005 |
| Class II genes | precedes | Polar flagellum | FliF is inserted at the incipient swarmer pole where it initiates flagellar assembly | Jenal & Shapiro 1996 |
| Class IV flagellins | precedes | Polar flagellum | The filament assembles from six flagellins; no single one is strictly required | Faulds-Pain et al. 2011 |
| PleD | activates | Flagellum ejection | pleD is required for efficient FliF removal and ejection of the flagellum | Aldridge & Jenal 1999 |
| Polar flagellum | precedes | Flagellum ejection | FliF is proteolysed at swarmer→stalked differentiation, coinciding with flagellum loss | Jenal & Shapiro 1996; Aldridge & Jenal 1999 |
| Major che operon | synthesizes | Chemoreceptor array | The che operon expresses mcpA; McpA localizes to the flagellated pole | Jones et al. 2001; Alley et al. 1992 |
| Chemoreceptor array | localizes / scaffolds | Polar flagellum | The receptor array lies tens of nm from the flagellar motor it controls | Briegel et al. 2008 |
- Class II genes gene-cluster — e.g. fliF, fliL, fliQ, fliP, flbD: MS ring, switch, flagellum-specific export apparatus and regulators. Anderson et al. 1995; Mangan et al. 1999; Wu et al. 1995; Boyd & Gober 2001
- Class III genes gene-cluster — e.g. flbG (hook operon), flgF, flgI, flgE: outer basal-body rings and hook; σ54/FlbD-dependent. Ramakrishnan & Newton 1990; Wu et al. 1995; Mangan et al. 1999
- Class IV flagellins gene-cluster — Six flagellins FljJ–FljO; transcribed by FlbD/σ54, translated only after the basal body–hook is complete. Faulds-Pain et al. 2011; Anderson & Newton 1997; Llewellyn et al. 2005
- Major che operon gene-cluster — Major chemotaxis operon (mcpA…); CtrA-dependent, σ54- and class II-independent, peaks in predivisional cells. Jones et al. 2001
- CtrA protein — Hand-off from core module: activates class II flagellar promoters and the major chemotaxis operon. Quon et al. 1996; Laub et al. 2002; Jones et al. 2001
- TipN protein — Birth-scar landmark at the new pole; positions TipF so the flagellum is built at that pole. Huitema et al. 2006; Lam et al. 2006
- TipF protein — c-di-GMP receptor (degenerate EAL); flagellum assembly factor recruiting switch proteins and PflI to the new pole. Huitema et al. 2006; Davis et al. 2013
- FlbD protein — NtrC-like σ54 activator encoded by class II flbD; acts via ftr elements on class III and IV promoters. Ramakrishnan & Newton 1990; Wu et al. 1995
- FliX protein — Trans-acting factor that binds FlbD; represses FlbD when the class II structure is absent. Muir & Gober 2004
- σ54 (RpoN) protein — σ54, placed at level II; required for class III transcription and for flagellum and stalk biogenesis. Anderson et al. 1995; Brun & Shapiro 1992
- FlbT protein — Negative regulator binding the fljK mRNA 5' UTR; blocks translation and promotes mRNA decay until the hook assembles. Mangan et al. 1999; Anderson & Gober 2000; Llewellyn et al. 2005
- FlaF protein — Cell-cycle-regulated protein required for fljK translation and filament assembly; opposes FlbT. Llewellyn et al. 2005
- PleD protein — Diguanylate cyclase response regulator; required for FliF degradation, flagellum ejection and efficient stalk formation. Aldridge & Jenal 1999; Hecht & Newton 1995; Paul et al. 2004
- Polar flagellum structure — Single flagellum assembled at the swarmer pole of the predivisional cell; FliF MS ring anchors it in the membrane. Jenal & Shapiro 1996; Faulds-Pain et al. 2011
- Chemoreceptor array structure — Polar McpA array, hexagonally packed near the motor; McpA is ClpX-dependently degraded at swarmer→stalked. Alley et al. 1992; Briegel et al. 2008; Tsai & Alley 2001
- Flagellum ejection process — At the swarmer→stalked transition FliF is degraded and the flagellum released; a stalk then grows (stalk module). Jenal & Shapiro 1996; Aldridge & Jenal 1999
Pili, holdfast and surface adhesion
Swarmer cells carry Tad (Cpa) pili and make the polysaccharide holdfast at the new pole. Pilin expression needs CtrA and PleC, and PodJ positions the pilus and holdfast machinery; surface contact sensed through pilus retraction and the flagellar motor triggers c-di-GMP-dependent holdfast synthesis via HfsJ, which HfiA inhibits.
The interactive diagram needs JavaScript; the parts and interactions are listed below.
Parts and interactions, with evidence
| From | Interaction | To | Note | Evidence |
|---|---|---|---|---|
| CtrA | activates transcription | PilA (pilA) | pilA promoter is activated late in the cell cycle under CtrA control | Skerker & Shapiro 2000 |
| PleC | activates | PilA (pilA) | PleC activity controls accumulation of the PilA pilin subunit | Viollier et al. 2002; Viollier et al. 2002 |
| PodJ | localizes / scaffolds | PleC | PodJ provides positional information for polar localization of PleC | Viollier et al. 2002; Hinz et al. 2003 |
| PodJ | localizes / scaffolds | cpa genes | PodJ is required for polar localization of the pilus assembly factor CpaE | Viollier et al. 2002 |
| PleC | localizes / scaffolds | cpa genes | PleC activity drives the asymmetric distribution of CpaE to one pole | Viollier et al. 2002 |
| PilA (pilA) | precedes | Tad pili | Timed pilin transcription controls when pili are assembled | Skerker & Shapiro 2000 |
| cpa genes | synthesizes | Tad pili | Cluster encodes pilus assembly proteins; CpaC/CpaE are polar before filament polymerization | Skerker & Shapiro 2000; Viollier et al. 2002 |
| Tad pili | activates | Holdfast | Resistance to pilus retraction is sufficient to stimulate holdfast synthesis | Ellison et al. 2017; Sangermani et al. 2019 |
| Surface contact | activates | DgcB | Surface-induced motor interference stimulates c-di-GMP production by DgcB | Hug et al. 2017 |
| DgcB | synthesizes | c-di-GMP | DgcB synthesizes c-di-GMP in the tactile response | Hug et al. 2017 |
| c-di-GMP | activates | HfsJ | c-di-GMP allosterically activates HfsJ for rapid holdfast synthesis | Hug et al. 2017 |
| c-di-GMP | activates | Tad pili | Intermediate c-di-GMP boosts pilus activity; peak levels drive pilus retraction | Sangermani et al. 2019 |
| HfiA | inhibits | HfsJ | HfiA directly targets the glycosyltransferase HfsJ | Fiebig et al. 2014 |
| HfsJ | synthesizes | Holdfast | HfsJ is required for holdfast production | Fiebig et al. 2014; Hug et al. 2017 |
| hfs genes | synthesizes | Holdfast | hfsDAB mutants make no holdfast; hfsG/hfsH are needed for synthesis | Smith et al. 2003; Toh et al. 2008 |
| HfaA/B/D anchor | binds | Holdfast | HfaA/HfaB/HfaD form a complex anchoring the holdfast to the cell | Hardy et al. 2010 |
| PodJ | localizes / scaffolds | HfaA/B/D anchor | Polar Hfa localization requires PodJ and holdfast secretion proteins | Hardy et al. 2010 |
| PleD | activates | Holdfast | Holdfast formation timing in swarmer cells depends on PleD | Levi & Jenal 2006 |
| Flagellum | activates transcription | HfiA | hfiA transcription falls in flagellar mutants (PleD-modulated), so they make holdfast early | Berne et al. 2018; Hershey et al. 2019 |
- cpa genes gene-cluster — Pilus assembly genes incl. secretin CpaC and assembly factor CpaE, which localize to one pole before pili polymerize. Skerker & Shapiro 2000; Viollier et al. 2002
- hfs genes gene-cluster — hfsDAB (export; Wza/GumC-like), hfsEFGH (repeat-unit synthesis, deacetylase) and hfsC polymerase. Smith et al. 2003; Toh et al. 2008
- HfaA/B/D anchor gene-cluster — Outer-membrane anchor complex tethering the holdfast to the pole and later the stalk tip. Hardy et al. 2010
- CtrA protein — Hand-off from core module: regulates the late-activated pilA promoter, timing pilus assembly. Skerker & Shapiro 2000
- PilA (pilA) protein — Major pilin subunit encoded in a seven-gene pilus cluster; PilA accumulation requires PleC activity. Skerker & Shapiro 2000; Viollier et al. 2002
- PodJ protein — Polar organelle development factor (two forms); localizes PleC, CpaE and the holdfast anchor to the new pole. Viollier et al. 2002; Hinz et al. 2003; Hardy et al. 2010
- PleC protein — Polar histidine kinase (core module link); controls PilA accumulation and asymmetric CpaE localization. Viollier et al. 2002; Viollier et al. 2002
- DgcB protein — Motor-associated diguanylate cyclase; makes c-di-GMP when surface contact interferes with the flagellar motor. Hug et al. 2017
- PleD protein — Diguanylate cyclase; timing of holdfast formation in swarmer cells is post-translational and PleD-dependent. Levi & Jenal 2006; Berne et al. 2018
- HfiA protein — 68-residue holdfast inhibitor binding HfsJ; cell-cycle regulated, and a nutritional override limiting adhesion. Fiebig et al. 2014
- HfsJ protein — Glycolipid glycosyltransferase required for holdfast; inhibited by HfiA, allosterically activated by c-di-GMP. Fiebig et al. 2014; Hug et al. 2017
- c-di-GMP small-molecule — Second messenger (c-di-GMP module); allosterically activates HfsJ and tunes pilus dynamics. Hug et al. 2017; Sangermani et al. 2019
- Tad pili structure — Polar swarmer pili with dynamic extension/retraction cycles; retraction pulls cells upright on surfaces. Skerker & Shapiro 2000; Ellison et al. 2017; Sangermani et al. 2019
- Holdfast structure — Polar GlcNAc-containing polysaccharide adhesin; single-cell detachment forces 0.11–2.26 µN. Smith et al. 2003; Tsang et al. 2006
- Flagellum structure — Hand-off from flagellum module: flagellum assembly feeds back to keep hfiA expressed (PleD-modulated). Berne et al. 2018; Hershey et al. 2019
- Surface contact process — Surface encounter, sensed as resistance to pilus retraction and as interference with the flagellar motor. Ellison et al. 2017; Hug et al. 2017
c-di-GMP oscillation and its outputs
c-di-GMP is low in G1 swarmer cells and rises at the G1→S transition, when the phosphodiesterase PdeA is degraded and the cyclases DgcB and PleD (activated by DivJ-dependent phosphorylation) act. The rising signal drives ShkA–TacA transcription, binds PopA and CckA to clear CtrA and allow replication, and activates TipF and HfsJ for polar morphogenesis.
The interactive diagram needs JavaScript; the parts and interactions are listed below.
Parts and interactions, with evidence
| From | Interaction | To | Note | Evidence |
|---|---|---|---|---|
| DivJ | phosphorylates | PleD | DivJ positively controls the in vivo phosphorylation of PleD | Aldridge et al. 2003 |
| PleC | inhibits | PleD | PleC modulates PleD phosphorylation negatively | Aldridge et al. 2003 |
| PleD | synthesizes | c-di-GMP | Phosphorylated PleD dimerizes, localizes to the pole and synthesizes c-di-GMP | Paul et al. 2004; Paul et al. 2007 |
| DgcB | synthesizes | c-di-GMP | Unopposed DgcB activity, with PleD, upshifts c-di-GMP at G1→S | Abel et al. 2011 |
| PdeA | hydrolyzes | c-di-GMP | PdeA's EAL domain hydrolyses c-di-GMP to pGpG; it antagonizes DgcB until G1→S | Christen et al. 2005; Abel et al. 2011 |
| CpdR | promotes degradation | PdeA | CpdR delivers PdeA to the ClpXP protease at the G1→S transition | Abel et al. 2011 |
| c-di-GMP | activates | ShkA | c-di-GMP binds the ShkA pseudo-receiver domain and stimulates the kinase | Kaczmarczyk et al. 2020 |
| ShkA | phosphotransfer | TacA | Phosphorelay ShkA→ShpA→TacA phosphorylates and activates TacA | Biondi et al. 2006; Kaczmarczyk et al. 2020 |
| TacA | activates transcription | Polar development | TacA with σ54 activates stalk genes in a G1/S-specific program | Biondi et al. 2006; Kaczmarczyk et al. 2020 |
| c-di-GMP | binds | PopA | c-di-GMP binding to PopA's GGDEF domain targets PopA to the cell pole | Duerig et al. 2009; Ozaki et al. 2014 |
| PopA | promotes degradation | CtrA | Polar PopA recruits CtrA via RcdA to the old pole for ClpXP proteolysis | Duerig et al. 2009; Ozaki et al. 2014 |
| c-di-GMP | inhibits | CckA | c-di-GMP binds CckA, inhibiting its kinase and stimulating its phosphatase activity | Lori et al. 2015 |
| c-di-GMP | activates | TipF | Rising c-di-GMP activates, stabilizes and polarizes TipF | Davis et al. 2013 |
| c-di-GMP | binds | DgrA | DgrA is a PilZ-type c-di-GMP receptor controlling flagellar motor function | Christen et al. 2007 |
| c-di-GMP | activates | HfsJ | c-di-GMP allosterically activates the holdfast glycosyltransferase HfsJ | Hug et al. 2017 |
| PleD | activates | Polar development | PleD GGDEF signalling is needed for FliF degradation, flagellum ejection and stalk formation | Aldridge & Jenal 1999; Aldridge et al. 2003 |
- DivJ protein — Hand-off from core module: stalked-pole histidine kinase that positively controls PleD phosphorylation. Aldridge et al. 2003
- PleC protein — Hand-off from core module: swarmer-pole histidine kinase that negatively modulates PleD phosphorylation. Aldridge et al. 2003
- PleD protein — Response regulator with GGDEF output; phosphorylation-driven dimerization activates c-di-GMP synthesis and polar localization. Hecht & Newton 1995; Paul et al. 2004; Paul et al. 2007
- DgcB protein — Diguanylate cyclase held in check by PdeA until G1→S; also a motor-associated surface sensor. Abel et al. 2011; Hug et al. 2017
- PdeA protein — GGDEF–EAL c-di-GMP phosphodiesterase (CC3396) activated by GTP; degraded by ClpXP via CpdR at G1→S. Christen et al. 2005; Abel et al. 2011
- CpdR protein — Hand-off from core module: response regulator that delivers PdeA to ClpXP in a phosphorylation-dependent way. Abel et al. 2011
- ShkA protein — Hybrid histidine kinase stimulated by c-di-GMP binding its pseudo-receiver; relays via ShpA to TacA; later proteolysed. Kaczmarczyk et al. 2020; Biondi et al. 2006
- TacA protein — σ54-dependent activator driving the G1/S-specific transcription program for morphogenesis and S-phase entry. Kaczmarczyk et al. 2020; Biondi et al. 2006
- PopA protein — PleD paralogue turned c-di-GMP effector; c-di-GMP targets it to the old pole, where it links to RcdA. Duerig et al. 2009; Ozaki et al. 2014
- CckA protein — Hand-off to core phosphorelay: essential kinase that c-di-GMP binding switches from kinase to phosphatase mode. Lori et al. 2015
- CtrA protein — Hand-off to core module: replication inhibitor degraded by ClpXP at the old pole at G1→S. Duerig et al. 2009; Abel et al. 2011
- TipF protein — Degenerate-EAL c-di-GMP receptor; activated, stabilized and polarized as c-di-GMP rises to nucleate the flagellum. Davis et al. 2013
- DgrA protein — PilZ-domain c-di-GMP receptor; high c-di-GMP or DgrA blocks motility by interfering with motor function. Christen et al. 2007
- HfsJ protein — Hand-off to pili-holdfast module: holdfast glycosyltransferase allosterically activated by c-di-GMP. Hug et al. 2017
- c-di-GMP small-molecule — Cyclic di-GMP; oscillates over the cycle (low in G1, upshift at G1→S) and is distributed asymmetrically at division. Abel et al. 2013; Christen et al. 2010; Lori et al. 2015
- Polar development process — Swarmer→stalked pole remodelling: flagellum ejection and stalk biogenesis. Aldridge & Jenal 1999; Aldridge et al. 2003; Biondi et al. 2006
Stress responses: GSR, SOS and starvation
The general stress response is a partner switch: stress kinases pass phosphate through MrrA and PhyK to PhyR, whose σ-like domain then sequesters the anti-σ NepR and frees σT. DNA damage delays division via SOS-induced SidA and SOS-independent DidA, while starvation and proteotoxic stress arrest the cycle through (p)ppGpp and Lon-dependent loss of DnaA.
The interactive diagram needs JavaScript; the parts and interactions are listed below.
Parts and interactions, with evidence
| From | Interaction | To | Note | Evidence |
|---|---|---|---|---|
| MrrA | phosphotransfer | PhyK | PhyK accepts phosphoryl groups from MrrA | Lori et al. 2018 |
| PhyK | phosphotransfer | PhyR | PhyK passes phosphate on to PhyR; PhyR phosphorylation is PhyK-dependent in vivo | Lori et al. 2018; Lourenço et al. 2011 |
| MrrA | phosphotransfer | LovK–LovR | MrrA also transfers phosphate to LovK | Lori et al. 2018 |
| LovK–LovR | represses | PhyR | LovK–LovR controls PhyR phosphorylation, draining phosphate away from the PhyK–PhyR branch | Foreman et al. 2012; Lori et al. 2018 |
| PhyR | binds | NepR | Phospho-PhyR's σ-like domain binds the anti-σ NepR (partner switch) | Herrou et al. 2010; Herrou et al. 2012; Lourenço et al. 2011 |
| NepR | inhibits | σT (EcfG) | NepR directly binds σT and negatively regulates its function | Lourenço et al. 2011 |
| σT (EcfG) | activates transcription | σT regulon | σT directly controls most of its regulon, induced e.g. by osmotic stress | Alvarez-Martinez et al. 2007; Lourenço et al. 2011 |
| σT (EcfG) | represses | CtrA | SigT mediates the carbon starvation-induced degradation of CtrA | Britos et al. 2011 |
| DNA damage | inhibits | LexA | Damage-induced LexA cleavage releases repression of SOS genes | Modell et al. 2014 |
| LexA | represses transcription | SidA | sidA belongs to the LexA-regulated SOS regulon | Modell et al. 2011; da Rocha et al. 2008 |
| DNA damage | activates transcription | DidA | didA is induced by DNA damage independently of SOS, via DriD | Modell et al. 2014 |
| DNA damage | inhibits | CtrA | DNA damage coordinately induces the SOS regulon and inhibits CtrA | Modell et al. 2011 |
| SidA | inhibits | FtsW / FtsN | SidA binds FtsW directly, preventing final constriction | Modell et al. 2011 |
| DidA | inhibits | FtsW / FtsN | DidA binds FtsN to block cytokinesis without disrupting divisome assembly | Modell et al. 2014 |
| SpoT | synthesizes | (p)ppGpp | SpoT synthesizes (p)ppGpp in response to carbon or nitrogen starvation | Lesley & Shapiro 2008; Boutte & Crosson 2011; Ronneau et al. 2016 |
| (p)ppGpp | promotes degradation | DnaA | SpoT/(p)ppGpp is required for starvation-triggered DnaA proteolysis in swarmer cells | Lesley & Shapiro 2008 |
| (p)ppGpp | stabilizes (protects from degradation) | CtrA | ppGpp/polyP keep CtrA in starved swarmers; mutants degrade CtrA and start replication | Boutte et al. 2012 |
| Lon | degrades | DnaA | Lon directly degrades DnaA; proteotoxic stress induces and activates Lon | Jonas et al. 2013; Leslie et al. 2015 |
- σT regulon gene-cluster — General stress regulon (~40 genes incl. sigU, sigR, envelope and stress genes), shared with PhyK/PhyR control. Alvarez-Martinez et al. 2007; Lourenço et al. 2011
- MrrA protein — Single-domain response regulator phosphorylated by ≥6 stress kinases; hub feeding PhyK→PhyR and LovK. Lori et al. 2018
- PhyK protein — Membrane histidine-kinase homolog (CC3474) essential for σT genes; acts as phosphotransferase from MrrA to PhyR. Lourenço et al. 2011; Lori et al. 2018
- PhyR protein — Anti-anti-σ with σ-like and receiver domains; receiver phosphorylation opens the σ-like domain to bind NepR. Herrou et al. 2010; Herrou et al. 2012
- NepR protein — Anti-σ factor that binds σT; switches to binding phospho-PhyR under stress. Lourenço et al. 2011; Herrou et al. 2012
- σT (EcfG) protein — ECF σ factor σT, master regulator of the general stress response; needed to survive osmotic and oxidative stress. Alvarez-Martinez et al. 2007; Lourenço et al. 2011
- LovK–LovR protein — LOV kinase LovK and receiver LovR; repress the GSR by acting as a phosphate sink; also modulate cell attachment. Foreman et al. 2012; Lori et al. 2018; Purcell et al. 2007
- CtrA protein — Hand-off to core module: inhibited after DNA damage; degraded in carbon starvation in a SigT-dependent way. Modell et al. 2011; Britos et al. 2011
- LexA protein — SOS repressor of ≥37 genes binding the GTTCN7GTTC operator; its cleavage after damage induces SOS genes. da Rocha et al. 2008; Modell et al. 2014
- SidA protein — 29-aa SOS-induced membrane protein; binds FtsW to block final constriction after DNA damage. Modell et al. 2011
- DidA protein — SOS-independent division inhibitor induced by DNA damage via the transcription factor DriD; binds FtsN. Modell et al. 2014
- FtsW / FtsN protein — Late divisome proteins driving septal wall synthesis (division-site module); targets of SidA and DidA. Modell et al. 2011; Modell et al. 2014
- SpoT protein — Sole RelA/SpoT homolog; ribosome-bound, makes (p)ppGpp on carbon or nitrogen (glutamine, via PTS-Ntr) starvation. Boutte & Crosson 2011; Lesley & Shapiro 2008; Ronneau et al. 2016
- DnaA protein — Hand-off to core module: unstable replication initiator; cleared on starvation (less translation, Lon) and proteotoxic stress. Gorbatyuk et al. 2005; Leslie et al. 2015; Jonas et al. 2013
- Lon protein — AAA+ protease degrading DnaA; induced, and allosterically activated by unfolded proteins, after DnaK loss or heat. Jonas et al. 2013; Leslie et al. 2015
- (p)ppGpp small-molecule — Alarmone; with polyphosphate keeps starved swarmer cells in G1 and extends the G1 phase. Boutte et al. 2012; Ronneau et al. 2016; Lesley & Shapiro 2008
- DNA damage process — DNA damage triggers the LexA-controlled SOS regulon and SOS-independent responses that delay division. Modell et al. 2011; Modell et al. 2014
Stalk biogenesis and specialization
The stalk is a thin extension of all envelope layers grown at the old pole after flagellum ejection. PopZ recruits SpmX, which recruits DivJ; bactofilins recruit the PG synthase PbpC, which anchors the stalk protein StpX, and diffusion barriers compartmentalize the stalk. PleD and ShkA–TacA/σ54 promote stalk growth; phosphate limitation lengthens it via Pst/PhoB.
The interactive diagram needs JavaScript; the parts and interactions are listed below.
Parts and interactions, with evidence
| From | Interaction | To | Note | Evidence |
|---|---|---|---|---|
| PopZ | recruits | SpmX | PopZ directly recruits SpmX to the developing stalked pole | Perez et al. 2017 |
| SpmX | recruits | DivJ | Localized SpmX recruits and stimulates the DivJ kinase | Radhakrishnan et al. 2008; Perez et al. 2017 |
| PopZ | activates | Stalk | PopZ affects polar stalk morphogenesis | Ebersbach et al. 2008 |
| PleD | activates | Stalk | pleD loss cuts stalk formation to ~25% of cells; constitutive PleD doubles stalk length | Aldridge & Jenal 1999; Aldridge et al. 2003 |
| ShkA | phosphotransfer | ShpA | Phosphotransfer profiling places ShpA downstream of the hybrid kinase ShkA | Biondi et al. 2006 |
| ShpA | phosphotransfer | TacA | ShpA phosphorylates and thereby activates TacA in vivo | Biondi et al. 2006 |
| TacA | activates transcription | StaR | TacA activates its regulon, which includes staR | Biondi et al. 2006 |
| σ54 (RpoN) | activates transcription | StaR | TacA collaborates with σ54 to activate stalk gene expression | Biondi et al. 2006 |
| StaR | activates | Stalk | staR regulates stalk length | Biondi et al. 2006 |
| BacA / BacB | recruits | PbpC | Bactofilin polymerization and membrane binding are needed to recruit PbpC to the stalked pole | Kühn et al. 2010; Liu et al. 2025 |
| PbpC | synthesizes | Stalk | Bactofilin-localized PG synthase acts at the stalked pole during stalk synthesis | Kühn et al. 2010; Hughes et al. 2013 |
| PbpC | localizes / scaffolds | StpX | PbpC anchors StpX to rigid outer-membrane components of the elongating stalk | Hughes et al. 2013 |
| StpX | localizes / scaffolds | Stalk | StpX is sequestered in the stalk (dispersed in stalkless mutants) and modulates elongation | Hughes et al. 2010 |
| Stalk diffusion barriers | localizes / scaffolds | Stalk | Barrier complexes prevent membrane and soluble protein exchange between stalk and body | Schlimpert et al. 2012 |
| PstSCAB | represses | PhoB | pst mutants make long stalks even in high phosphate, and this requires phoB | Gonin et al. 2000 |
| PhoB | activates transcription | PstSCAB | pstS transcription depends on phoB | Gonin et al. 2000 |
| PhoB | activates | Stalk | PhoB is required for stalk elongation in response to phosphate starvation | Gonin et al. 2000 |
- PstSCAB gene-cluster — High-affinity phosphate transporter; pst mutants make long stalks; PstS (not PstA) is present in the stalk. Gonin et al. 2000; Wagner et al. 2006
- PopZ protein — Polar matrix; directly binds SpmX (bridging to DivJ) and affects polar stalk morphogenesis. Perez et al. 2017; Ebersbach et al. 2008
- SpmX protein — Lysozyme-homolog polarity protein; accumulates at the future stalked pole, oligomerizes and recruits/stimulates DivJ. Radhakrishnan et al. 2008; Perez et al. 2017
- DivJ protein — Hand-off to core module: stalked-pole histidine kinase that phosphorylates DivK; recruited by SpmX. Radhakrishnan et al. 2008; Perez et al. 2017
- PleD protein — Diguanylate cyclase; without it only ~25% of cells build a stalk; constitutive PleD doubles stalk length. Aldridge & Jenal 1999; Aldridge et al. 2003
- ShkA protein — Hybrid histidine kinase heading the stalk phosphorelay; stimulated by c-di-GMP (c-di-GMP module). Biondi et al. 2006; Kaczmarczyk et al. 2020
- ShpA protein — Histidine phosphotransferase relaying phosphate from ShkA to TacA; required for stalk biogenesis. Biondi et al. 2006
- TacA protein — σ54-dependent activator required for cell-cycle-regulated stalk biogenesis. Biondi et al. 2006
- σ54 (RpoN) protein — σ54; needed for both stalk and flagellum biogenesis; rpoN transcription rises with stalk formation. Brun & Shapiro 1992; Biondi et al. 2006
- StaR protein — TacA-regulon gene product that regulates stalk length. Biondi et al. 2006
- BacA / BacB protein — Bactofilins: polymerizing, membrane-bound sheet near the stalked pole; scaffold for a stalk PG synthase. Kühn et al. 2010; Liu et al. 2025
- PbpC protein — Bifunctional PBP recruited by BacA; acts at the stalked pole in stalk synthesis and anchors StpX. Kühn et al. 2010; Liu et al. 2025; Hughes et al. 2013; Strobel et al. 2014
- StpX protein — Bitopic stalk membrane protein; modulates stalk elongation; PbpC-anchored; role in copper/zinc responses. Hughes et al. 2010; Hughes et al. 2013
- PhoB protein — Pho regulon response regulator; required for stalk elongation in phosphate starvation and for pstS transcription. Gonin et al. 2000
- Stalk diffusion barriers structure — Complexes of ≥4 proteins spanning the stalk that block protein exchange between stalk and cell body. Schlimpert et al. 2012
- Stalk structure — Thin envelope extension at the old pole; takes up and hydrolyses organic phosphate; up to 30× longer in low phosphate. Gonin et al. 2000; Wagner et al. 2006; Hughes et al. 2010