1984; Oliver and Weir, 1985; Ruhen et al., 1980; Schwarzmann and Boring ... major players involved in the P. aeruginosa and E. coli RIP cas- cade (Table 4.7.1)Β ...
C H A P T E R 4.7
Posttranslational regulation of antisigma factors of RpoE: a comparison between the Escherichia coli and Pseudomonas aeruginosa systems Sundar Pandey1 , Kyle L. Martins2 , and Kalai Mathee2 1
Department of Biological Sciences, College of Arts & Sciences, Florida International University, Miami, Florida, USA Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA
2
4.7.1 Introduction Pathways for sensing environmental stress are key for bacterial survival. In the absence of alerting mechanisms, environmental signals would not reach the cytoplasmic machinery responsible for affecting changes in the cells necessary for survival. One roadblock in the transmission of external signals is the presence of two membranes in Gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa. Each membrane necessitates a transduction pathway capable of receiving and transmitting a signal across, it in order for the cell to respond appropriately. As outer membrane integrity is of foremost concern for Gram-negative bacteria, many pathways have evolved to sense and respond to stress in the membranes (Rowley et al., 2006). One well-studied pathway in E. coli is the envelope stress response (see Section 18) that utilizes the alternative sigma factor RpoE (ΟE ). RpoE was first described to be responsible for survival under high-temperature conditions where traditional sigma factors could not operate (Erickson and Gross, 1989; Hiratsu et al., 1995). An RpoE homolog was subsequently identified in P. aeruginosa, termed AlgT/U, to be the master regulator of alginate production (Flynn and Ohman, 1988a,1988b; Martin et al., 1993a). P. aeruginosa has been increasingly recognized as the most important pathogen in the airways of cystic fibrosis patients. Once the bacteria have colonized the lungs, infections are highly resistant even to aggressive antibiotic therapy (da Silva Filho et al., 2001). The bacterial hallmark of a chronic infection is the appearance of P. aeruginosa strains with a βmucoidβ phenotype (Alg+ ) due to overproduction of alginate, a capsule-like polysaccharide with antiphagocytic and immunosuppressive properties that protects bacteria from host defenses and antibiotics (Baltimore and Mitchell, 1980; Govan and Fyfe, 1978; Meshulam et al.,
1984; Oliver and Weir, 1985; Ruhen et al., 1980; Schwarzmann and Boring, 1971). The importance of alginate in virulence was confirmed in three different studies (Boucher et al., 1997; Song et al., 2003; Yu et al., 1995) where the severity of the outcome was correlated with alginate production. RpoE homologs are members of the extracytoplasmic function (ECF) sigma factors (Lonetto et al., 1994; see Chapter 2.6). The stress signals initiate a Regulated Intramembrane Proteolytic (RIP) cascade that eliminates an inner membrane negative regulator (i.e., an antisigma factor freeing RpoE). The RIP cascade is common to many bacteria, including Bacillus subtilis (Schobel et al., 2004; Zellmeier et al., 2006), Mycobacterium tuberculosis (Sklar et al., 2010), and Xanthomonas campestris (Bordes et al., 2011). This chapter will elucidate the role of the major players involved in the P. aeruginosa and E. coli RIP cascade (Table 4.7.1) and the signals involved. For simplicity, the nomenclature in column 2 and column 6 of Table 4.7.1 will be adopted in this chapter. Although the members of the E. coli and P. aeruginosa RIP cascade are functionally conserved, there is a wide variation in sequence homology between orthologs (Table 4.7.2).
4.7.2 Extracytoplasmic stress sigma factor πE : AlgT/U and RpoE P. aeruginosa and E. coli RpoE share 66% homology with each other (Lonetto et al., 1992). E. coli RpoE has been found to restore the mucoid (Alg+ ) phenotype in P. aeruginosa algT/U mutant (Yu et al., 1995). However, there is no in vivo experimental evidence as to whether algT/U complements the function of rpoE in E. coli, although AlgT/U has been shown to transcribe E. coli RpoE-dependent promoters in vitro (Hershberger et al., 1995). Activation of alternative sigma factors in
Stress and Environmental Regulation of Gene Expression and Adaptation in Bacteria, First Edition. Edited by Frans J. de Bruijn. Β© 2016 John Wiley & Sons, Inc. Published 2016 by John Wiley & Sons, Inc.
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Section 4: Sigma factors and stress responses
Table 4.7.1 List of proteins involved in RpoE regulation. P. aeruginosa Locus tag
Protein
PA0762 PA0763 PA0764 PA0765 PA0766 PA4446 PA3649 PA4033 PA1802 PA1801 PA3326 PA4427 PA4428
AlgT/U MucA MucB MucC MucD AlgW MucP MucE ClpX ClpP ClpP2 SspB SspA
E. coli
Alternative name
Size (aa)
RpoE/Ο22
193 194 316 151 474 389 450 89 426 213 201 135 205
AlgN AlgM AlgY/HtrA
ClpP1
Locus tag
Protein
Alternative name
Size (aa)
ECK2571 ECK2570 ECK1569 ECK2568 ECK0160 ECK3224 ECK0175 No homologs ECK0432 ECK0431
RpoE RseA RseB RseC DegP DegS RseP
Ο24 /ΟE /SigE MclA/YfiJ MclB MclC HtrA/Ptd/Do HhoB/HtrH YaeL/EcfE
191 216 318 159 475 355 450
Sigma factor Anti-sigma factor Negative regulator
ClpX ClpP
LopP/WseA
424 201
ATPase subunit of the protease Proteolytic subunit of the protease
ECK3217 ECK3218
SspB SspA
Ssp/Pog
165 212
Stringent starvation protein Stringent starvation protein
P. aeruginosa and E. coli are controlled both at the level of transcriptional initiation and posttranslationally. This chapter focuses on the posttranslational control of this sigma factor. The rpoE operon contains four genes that either positively or negatively regulate its activity in E. coli (Missiakas et al., 1997). The three open reading frames downstream of rpoE encode regulators of sigma E and are thus named rseA, rseB, and rseC (De Las PeΛnas et al., 1997; Missiakas et al., 1997). In the case of P. aeruginosa, algT/U is part of a five-gene operon containing algT/U, mucA, mucB, mucC, and mucD (Boucher et al., 1996; Ohman et al., 1996). These Muc proteins regulate AlgT/U activity.
4.7.3 E. coli RseA and P. aeruginosa MucA β the antisigma factors Both RseA and MucA are negative regulators of the alternative sigma factors RpoE and AlgT/U, respectively, and are referred
Product name
Serine endoprotease Site-1 protease; HtrA family Site-2 protease; Zn-dependent
to as antisigma factors. For more details, analyses of other antisigma factors can be found in Hughes and Mathee (1998). Although these two proteins are functional equivalents, they share very little sequence homology (Table 4.7.2). Transposon insertions in rseA resulted in a 12-fold increase (Missiakas et al., 1997), whereas deletion mutants exhibited a 25-fold induction of RpoE activity (De Las PeΛnas et al., 1997). This large upregulation upon the loss of rseA suggested that the major role of RseA is to act as a negative regulator of RpoE activity. Inactivation of mucA in P. aeruginosa resulted in a mucoid phenotype suggesting that MucA is a negative regulator of alginate production (Fyfe and Govan, 1980; Govan and Fyfe, 1978; Martin et al., 1993c; Mathee et al., 1999). Mapping and sequence analysis showed that mucA was located directly downstream of algT/U (Martin et al., 1993a,b,c). Both RseA and MucA are localized to the inner membrane with the N-terminus in the cytoplasm and C-terminus
Table 4.7.2 Comparison of E. coli and P. aeruginosa homologs involved in the anti-Ο factor (RseA and MucA, respectively) proteolysis.
P. aeruginosa PAO1
E. coli K12
AlgT/U MucA MucB MucC MucD AlgW MucP CIpX CIpP CIpP2 SspA SspB
RpoE
RseA
RseB
RseC
DegP
DegS
RseP
ClpX
ClpP
SspA
SspB
66.0 14.4 19.4 15.9 22.0 17.4 17.3 23.0 12.0 16.6 13.2 16.3
7.8 28.3 16.2 17.2 19.4 17.6 17.6 15.3 11.3 12.6 11.5 19.2
18.7 22.2 27.6 21.2 17.9 15.8 19.8 15.1 16.1 19.4 20.0 20.0
15.2 18.2 29.9 30.0 15.0 23.9 23.2 19.5 18.9 19.6 20.1 18.0
20.7 16.1 17.2 23.2 39.2 36.8 10.2 16.2 18.8 14.9 18.6 21.5
18.8 15.0 11.4 26.5 33.4 46.3 16.7 17.9 17.4 19.4 17.6 20.8
21.2 18.6 19.5 24.5 15.4 17.2 46.9 12.6 19.7 16.4 19.5 22.2
25.4 17.0 18.4 22.5 15.2 14.3 11.4 76.6 17.4 22.6 21.2 18.5
16.2 13.3 17.0 10.7 23.2 20.3 17.9 19.3 69.6 41.5 12.6 16.3
9.3 14.9 19.3 17.3 16.9 18.4 23.5 21.2 13.2 14.2 53.9 20.0
15.7 13.3 18.1 13.3 19.3 18.7 22.4 17.5 14.5 15.7 15.2 53.3
The numbers refer to percentage homology as determined using ClustalW. The shaded boxes compare the functional homologs. The protein sequences of E. coli and P. aeruginosa were retrieved from ecogene.com and pseudomonas.com, respectively.
Chapter 4.7: Comparison of E. coli and P. aeruginosa RIP cascades
in the periplasm (De Las PeΛnas et al., 1997; Lewenza et al., 2005; Mathee et al., 1997; Missiakas et al., 1997). Membrane preparations of RseA-overproducing bacteria showed RpoE co-eluted with RseA (Missiakas et al., 1997). Pull-down experiments using RpoE-specific antibodies showed RseA and RpoE co-immunoprecipitating at a molar ratio close to 1:1 (Missiakas et al., 1997). In the case of P. aeruginosa, co-expression of MucA and AlgT/U followed by cross-linking suggested MucA and AlgT/U interact directly (Schurr et al., 1996). This was supported by the cofractionation of MucA and AlgT/U in glycerol sedimentation experiments (Xie et al., 1996).
4.7.4 E. coli RseB and P. aeruginosa MucB β anti-antisigma factors RseB and MucB share only 27.6% homology (Table 4.7.2); however, they are functional equivalents that interact with the antisigma factors and subsequently affect alternative sigma factor activity. Deletion of rseB in E. coli resulted in an increase in rpoE expression, whereas loss of mucB resulted in alginate production (Goldberg et al., 1993; Martin et al., 1993a,b). These findings clearly argued that RseB and MucB are negative regulators of RpoE and AlgT/U, respectively. Both RseB and MucB are localized to the periplasm (Mathee et al., 1997; Missiakas et al., 1997; Schurr et al., 1996). Direct interaction between RseB and MucB with their cognate antisigma factors RseA and MucA, respectively, has been demonstrated (Missiakas et al., 1997; Rowen and Deretic, 2000). Specifically, RseB and MucB were found to interact with the periplasmic C-terminal domain of their cognate antisigma factors (Cezairliyan and Sauer, 2007; Wood and Ohman, 2009). RseB is present as a dimer that protects RseA from cleavage by DegS (Cezairliyan and Sauer, 2007; Wollman and Zeth, 2007). In the case of MucB, it exists in both monomeric and dimeric forms; however, only the dimer binds to MucA (Cezairliyan and Sauer, 2009). The RseAβRseB interaction appears to stabilize RseA (Ades et al., 1999) and strengthens RseAβs bond with RpoE (Collinet et al., 2000). Coaggregation of RseB with misfolded proteins suggests that it may act as a stress sensor, which may allow RseB to release from RseA to initiate the RIP cascade leading to RpoEdependent activity (Collinet et al., 2000).
4.7.5 E. coli RseC and P. aeruginosa MucC Although both E. coli rseC and P. aeruginosa mucC are the third gene in their respective rpoE operons, they share only 30% homology. The role of RseC and MucC is ambiguous, and little is currently known about the exact cellular function of these members of the rpoE and algT/U operons (Boucher et al., 1997; De Las PeΛnas et al., 1997; Missiakas et al., 1997; Ohman et al., 1996).
363
4.7.6 E. coli DegP and P. aeruginosa MucD E. coli DegP and P. aeruginosa MucD share 39% homology (Table 4.7.2). The presence of mucD in the algT/U operon suggests that MucD should play a role in the posttranslational regulation of AlgT/U. In the case of E. coli, degP is not present in the rpoE operon (Strauch and Beckwith, 1988). Expression of both degP and mucD is under the control of RpoE and AlgT/U, respectively (Boucher et al., 1996; Dartigalongue et al., 2001; Erickson and Gross, 1989; Lipinska et al., 1988; Ohman et al., 1996; Wang and Kaguni, 1989). Although mutations in degP had no effect on E. coli rpoE transcription, DegP is required for its growth at elevated temperatures (Lipinska et al., 1989, 1990). Both null and point mutations of mucD in non-mucoid PAO1 resulted in a mucoid phenotype conversion (Boucher et al., 1996; Wood and Ohman, 2006). Alkaline-phosphatase fusion of DegP and MucD showed them residing in the periplasm (Lewenza et al., 2005; Strauch et al., 1989). The major role of both DegP and MucD is to degrade misfolded proteins from the periplasm (Strauch and Beckwith, 1988; Wood and Ohman, 2009) that may indirectly regulate RseB and MucB allowing it to re-interact with their cognate antisigma factors.
4.7.7 E. coli DegS and P. aeruginosa AlgW DegS and AlgW share substantial homology (Table 4.7.2). They are also members of the HtrA family of serine proteases (Pallen and Wren, 1997). DegS and AlgW are also known as site-1 proteases (S1Ps), which cleave antisigma factors on their periplasmic sides (Dalbey et al., 2012; Qiu et al., 2007). DegS is an inner membrane protein with a large periplasmic domain (Alba et al., 2002; Waller and Sauer, 1996). Based on sequence homology, AlgW is also presumed to be an inner membrane protein with a single transmembrane domain. DegS initiates the first cleavage of RseA, leading to an eventual release of RpoE to initiate transcription (Ades et al., 1999; Alba et al., 2002). DegS cleaves between Val148 and Ser149 in the transmembrane domain of RseA adjacent to the periplasmic side (Walsh et al., 2003). AlgW primarily cleaves MucA between Ala136 and Gly137 (Cezairliyan and Sauer, 2009). DegS binding of the Cterminal -YXF motif of misfolded outer membrane proteins (OMPs) activates it to cleave RseA (Walsh et al., 2003). In P. aeruginosa, this process appears to be initiated in response to increased expression of mucE that encodes an outer membrane associated small protein with a specific C-terminal -WVF motif (Qiu et al., 2007).
4.7.8 E. coli RseP and P. aeruginosa MucP Both RseP and MucP are site-2 proteases (S2Ps), which are membrane-bound zinc metalloproteinases involved in the
Section 4: Sigma factors and stress responses
(a)
(b)
Outer membrane
Outer membrane
Misfolded OMP Periplasm
1
MucE
PDZ
Y X F
?
Periplasm
1
PDZ
W V F
?
RseB 2
3
MucA
Algw
RseP
PDZ
RseA
DegS
Inner membrane
MucB
2
PDZ
Inner membrane
MucP
364
3
RpoE
AlgT/U
4
4
SspB
SspA
5
RpoE
ClpP
AlgT/U
6
ClpX
ClpP
5
ClpX
RpoE
6 AlgT/U
ClpP2 7
? RpoE
7
AlgT/U
RNAP
RNAP
2
2
Figure 4.7.1 Proposed model for the antisigma factor proteolysis in (a) E. coli and (b) P. aeruginosa. The model is based on currently available data. (a) The steps for E. coli are outlined as follows. (1) The βYXF C-terminal motif exposed in misfolded OMPs binds to the PDZ domain of DegS, activating its proteolytic domain. DegP may degrade misfolded OMP proteins prior to their interaction with DegS, perhaps preventing DegS activation. (2) Based on the P. aeruginosa system, RseB dissociates to allow site-1 proteolysis of RseA at its periplasmic side by DegS. (3) The removal of C-terminal RseA allows for site-2 proteolysis at its cytoplasmic side by RseP. It has been postulated that RseP access to RseA can also be prevented by RseB. (4) RseP activity releases RpoE with a fragment of RseA bound to it. (5) SspB binds to and brings the RseA fragment to the ClpXP proteasome. (6) ClpXP degradation of β² the RseA fragment releases free RpoE. (7) Free RpoE directs RNA polymerase that is made of five subunits (Ξ±2 Ξ²Ξ² Ο) to initiate transcription of the RpoE regulon. (b) The model is based on the available data and is, in part, inferred from the E. coli system. The steps involved are as follows. (1) The βWVF motif on MucE binds to the AlgW PDZ domain, activating its proteolytic activity. MucD is hypothesized to inhibit the interaction of MucE with AlgW, as well as bind misfolded proteins. (2) Activated AlgW cleaves the periplasmic domain of MucA, releasing MucB along with a C-terminal fragment of MucA. (3) MucP induces site-2 proteolysis of MucA at the cytoplasmic side, releasing AlgT/U with a small N-terminal fragment of MucA attached. (4) Based on the E. coli system, SspA is proposed to be the adaptor molecule that brings AlgT/U with the MucA fragment to ClpXP. (5,6) The MucA fragment is β² removed from AlgT/U by the ClpXP proteasome. The role of the ClpP2 homolog is not clear. (7) Free AlgT/U directs RNA polymerase (Ξ±2 Ξ²Ξ² Ο) to initiate transcription of the AlgT/U regulon.
proteolytic activation of regulatory factors for sterol biosynthesis and for stress responses (Kanehara et al., 2001; Kinch et al., 2006; Qiu et al., 2007). RseP and MucP were both identified based on sequence homology to other S2Ps (Kanehara et al., 2001; Qiu et al., 2007). RseP is essential in E. coli as depletion causes a rapid loss of viability, cell elongation, and growth cessation (Kanehara et al., 2001). RseP is an inner membrane protein with four transmembrane domains with both the N- and C-termini lying in the periplasm (Kanehara et al., 2001). RseP also contains two periplasmic PDZ domains involved in its regulation (Inaba et al., 2008; Kanehara et al., 2003). Our analysis using TMHMM shows MucP possessing a similar domain structure to RseP. Cleavage of RseA by RseP was confirmed using in vitro assays (Akiyama et al., 2004). The
regulated proteolysis of RseA requires a functional PDZ domain of RseP (Kanehara et al., 2003). Indirect genetic evidence for MucP cleavage of MucA leading to AlgT/U expression has been shown using mutant strains (Damron and Yu, 2011; Qiu et al., 2007). No direct interaction with MucP and MucA has been demonstrated.
4.7.9 E. coli and P. aeruginosa ClpXP After RseP cleavage of RseA, a small fragment of RseA remains attached to RpoE (De Las PeΛnas et al., 1997; Missiakas et al., 1997). The removal of this RseA cytoplasmic fragment requires SspB and ClpXP (Flynn et al., 2004). SspB was found to bind
Chapter 4.7: Comparison of E. coli and P. aeruginosa RIP cascades
to both the amino-terminus of RseA as well as ClpX, thereby bringing the fragment close enough to the ClpXP protein complex to allow for RseA fragment degradation (Flynn et al., 2004). In P. aeruginosa, there are two ClpP homologs, ClpP (PA1801) and ClpP2 (PA3326). Mutagenesis of clpX, clpP, and clpP2 individually resulted in the loss of a mucoid phenotype (Qiu et al., 2008). P. aeruginosa also harbors the sspAB (PA4426βPA4427) operon (Yin et al., 2013). Unlike E. coli, SspA appears to play a role in alginate production (Yin et al., 2013). A direct interaction between the MucA fragment and ClpXP or SspA has yet to be demonstrated.
4.7.10 RIP models for E. coli and P. aeruginosa Many questions remain unanswered. However, based on the findings in this chapter, the following model is proposed for P. aeruginosa (Figure 4.7.1a) and E. coli (Figure 4.7.1b). 4.7.10.1 E. coli RIP cascade Misfolded OMP peptides with exposed C-terminal -YQF motifs bind to the PDZ domain of DegS, allowing cleavage of RseA at the periplasm. It is also presumed that misfolded peptides competitively prevent RseB binding RseA, allowing cleavage of RseA by DegS. Alternatively, it has been postulated that RseB hinders RseP recognition of RseA. Following cleavage by DegS, RseP cleaves RseA at the cytoplasm, releasing RpoE with an N-terminal fragment of RseA. This N-terminal fragment of RseA is removed by SspBβClpXP, releasing the free RpoE to initiate transcription of the RpoE regulon. 4.7.10.2 P. aeruginosa RIP cascade Similar to the E. coli system, MucA is sequentially degraded by AlgW and MucP. The C-terminal -WVF motif of MucE has been shown to prime the AlgW protease to initiate the cleavage of MucA. Direct cleavage of MucA by MucP, or interaction of ClpXP or SspA/B, has not been demonstrated, but inferred from genetic data and by comparison to the E. coli system. In P. aeruginosa, SspB appears to play a role in this pathway. Free AlgT/U activates all the genes in the alg regulon, leading to alginate production.
4.7.11 Conclusion The regulatory cascade is initiated by an outer membrane component that senses external stress and transfers the signals to a periplasmic component that triggers the RIP cascade, ultimately resulting in the release of RpoE. In this cascade, most proteins in the inner membrane have been characterized, and a number of periplasmic proteins have been identified. However, it is not yet
365
clear how the periplasmic proteins are activated, who their targets are, or how they interact with the RIP cascade. Additionally, nothing is yet known about proteins in the outer membrane. It is believed that identifying outer membrane components would have great potential as pharmaceutical targets in the treatment of pathogens such as P. aeruginosa.
Acknowledgements This study was in part supported by National Science Foundation IIP-1237818 (PFI-AIR: CREST-I/UCRC-Industry Ecosystem to Pipeline Research) (KM), Florida International University (FIU) Bridge Funding (KM), a FIU Herbert Wertheim College of Medicine Graduate Assistantship (KLM), and a FIU Presidential Fellowship (SP). We are extremely grateful to Christopher Romero and Camila Delgado (FIU undergraduates) for contributing to the figures.
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Chapter 4.7: Comparison of E. coli and P. aeruginosa RIP cascades
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