The invasion-associated type-iii protein secretion system in Salmonella a review1

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1 Gene 192 (1997) The invasion-associated type-iii protein secretion system in Salmonella a review1 Carmen M. Collazo, Jorge E. Galán * Department of Molecular Genetics and Microbiology, School of Medicine, State University of New York at Stony Brook, Stony Brook, NY , USA Received 26 February 1996; accepted 20 September 1996; Received by T.F. Meyer Abstract The genetic determinants that confer upon Salmonella the ability to enter non-phagocytic cells are largely encoded in a pathogenicity island located at centisome 63 of the bacterial chromosome. Molecular genetic analysis has revealed that this region encodes a specialized protein secretion system that mediates the export and/or translocation of putative signaling proteins into the host cell. This protein secretion system, which has been termed type III or contact-dependent, has also been identified in other plant and animal pathogens that have, in common, the ability to interact with eukaryotic host cells in an intimate manner Elsevier Science B.V. Keywords: Bacterial pathogenesis; Bacteria-host cell interaction; Virulence; Pathogenicity island; Chaperone 1. Introduction matory cytokines. Both events are important in the pathogenesis of Salmonella spp. This review will focus Salmonella spp. are facultative intracellular pathogens on the molecular genetic basis of the Salmonella determithat engage the host cell in a remarkable two-way nants involved in the bacteria host cell interaction, and biochemical interaction as part of their pathogenic cycle. in particular, the components and targets of the special- This intimate interaction is followed by overt responses ized protein secretion system that is activated during from both the bacteria and the host cell. Central to this interaction. For a recent discussion of other subjects these responses is the activation in Salmonella spp. of a related to the interactions of Salmonella with host cells, specialized protein secretion system that directs the readers are referred to other reviews ( Finlay, 1994; export of a variety of proteins and, in some cases, their Galán, 1994, 1995). translocation into the host cell. These proteins, either directly or indirectly, stimulate signal transduction pathways in the mammalian cell that lead to a variety of 2. General features of the type-iii protein secretory host-cell responses, such as membrane ruffling and the systems activation of various transcription factors (reviewed in Galán, 1994, 1995). Membrane ruffling ultimately results It is now recognized that several animal and plant in bacterial uptake into the host cell and the concomitant pathogens use a specialized protein secretion system nuclear responses lead to the production of pro-inflam- termed either type-iii or host-cell contact-dependent for the secretion and/or delivery of virulence determinants (Salmond and Reeves, 1993; Van Gijsegem et al., 1993). * Corresponding author. Tel ; Fax ; General features of this system include: (1) the secreted proteins do not have a typical amino-terminal sequence 1 Presented at the Workshop on Type-4 Pili Biogenesis, Adhesins, characteristic of proteins exported in a sec-dependent Protein Export, and DNA Import, Schloss Ringberg, Germany, manner; (2) the export machinery directs the transloca- November tion of the target proteins through two membranes Abbreviations: C, carboxy; E., Escherichia; N, amino; P., without cleavage of their amino termini; and ( 3) an Pseudomonas; S., Salmonella; TM, transmembrane; Tn, transposon. inducing extracellular signal, usually resulting from the /97/$ Elsevier Science B.V. All rights reserved PII S (96)

2 52 C.M. Collazo, J.E. Galán / Gene 192 (1997) interaction with host cells, is required for complete 3. Components of the type-iii secretory machinery in activation of the secretory apparatus. Some of the Salmonella proteins that comprise these systems share homologies with polypeptides involved in the flagellar assembly The type-iii secretory machinery is organized as a process in both Gram+ and Gram microorganisms complex of proteins that presumably span the inner and (Dreyfus et al., 1993). Targets of these secretion systems outer membranes. In addition, there are cytoplasmic have been identified in several bacterial pathogens. These components which are involved in different aspects of include the Yop proteins of Yersinia (Straley et al., the secretion process such as energy transduction, pro- 1993); the Ipa (Sansonetti, 1992), VirA ( Uchiya et al., tection of the exported proteins from premature degra- 1995), and IpgD ( Allaoui et al., 1993) proteins of dation, and regulation of the invasion/secretion process. Shigella; the EaeB protein of enteropathogenic Escherichia coli (EPEC) (Donnenberg et al., 1993); and the Harpins (He et al., 1993; Wei et al., 1992) and Pop 3.1. The outer membrane proteins (Arlat et al., 1994) proteins from several plant At least three putative outer membrane components pathogens. of this machinery have been identified in type-iii sys- Type-III secretion systems differ from other secretion tems. In Salmonella, these incude the InvG ( Kaniga pathways in Gram microorganisms such as the type-i et al., 1994), PrgH and PrgK proteins (Pegues et al., system, exemplified by the E. coli hemolysin ( Holland 1995). InvG is a member of the PulD family of proteins et al., 1990), or the general secretory pathway (type II) and it is the only component identified so far that shares exemplified by the pullulanase export system (Pugsley, homology with components of type-ii protein secretion 1993). Proteins exported in the type-ii pathway are systems. However, this homology is restricted to a translocated through the inner membrane via the sec- domain in the C-terminus, which suggests that this dependent general export machinery and then trans- protein is organized in a modular fashion and that this ported across the outer membrane by means of a conserved domain might be involved in localizing the specialized secretory apparatus (Pugsley et al., 1991). protein to the outer membrane. InvG has been shown In contrast, protein secretion via the type-i pathway is to play an essential role in bacterial uptake and in sec-independent, although it requires the function of at protein secretion ( Kaniga et al., 1994). Based on studies least three accessory proteins ( Holland et al., 1990). involving other members of the PulD family such as the The genetic information encoding the components piv protein of filamentous phage, it is likely that InvG and targets of the type-iii secretory pathway in may be a multimeric protein that forms an outer mem- Salmonella is located in a contiguous region of the brane channel through which the secreted proteins exit chromosome at centisome 63, which constitutes an the bacterial cell ( Russel, 1995; Kazmierczak et al., example of a pathogenicity island (Mills et al., 1995) 1994). The conservation of the InvG/PulD homologs in ( Fig. 1). Other type-iii systems are also known to be the type-ii, type-iii, and phage-assembly systems sugencoded in either discrete chromosomal regions or in gests that these proteins play a key role in the translocavirulence associated plasmids. These observations, in tion of polypeptides across the outer membrane. conjunction with the consistent finding that the G+C PrgH and PrgK contain structural motifs characteriscontent of these regions is significantly different from tic of the processing site of lipoproteins (Pegues et al., that of the chromosome of the host microorganism, 1995). These lipoproteins are widely conserved since suggest that these genetic determinants have their origins they have been found in all of the type-iii systems in a common ancestor (Galán et al., 1992; Ginocchio studied so far. PrgK shares sequence homology with the et al., 1992; Groisman and Ochman, 1993). MxiJ (Allaoui et al., 1992) and YscJ (Michiels et al., Fig. 1. Invasion region at centisome 63 in the Salmonella chromosome. Vertical arrows indicate the boundaries of the pathogenicity island. Horizontal arrows indicate the direction of the transcription of the corresponding open reading frames. For a more detailed description of the genes present in the region, refer to the text and to Table 1.

3 C.M. Collazo, J.E. Galán / Gene 192 (1997) ) proteins of Shigella and Yersinia, respectively Energizer of the secretion process PrgH is homologous to the Shigella MxiG protein (Allaoui et al., 1995). The genes encoding these proteins Another very conserved member of the type-iii secretion are part of the prghijk operon which has been proposed apparatus is a protein that shares considerable to be involved in protein secretion based on sequence homology with the b subunit of the F F ATPases. Such 0 1 homologies to the Yersinia and Shigella systems (Pegues a protein in Salmonella is InvC, which has been shown et al., 1995). However, non-polar mutations in each in biochemical studies to have ATPase activity gene of this operon are required in order to clearly (Eichelberg et al., 1994). A site directed mutant in the establish their involvement in both bacterial entry and catalytic domain of InvC lacked ATPase activity and protein export. Thus, at least two determinants encoded was unable to complement a non-invasive S. typhimu- by the prg locus are likely to be outer membrane proteins rium strain carrying a null mutation in the invc gene. that play an important role in bacterial internalization These observations suggest a role for InvC in energizing and protein secretion. the translocation process. A group of proteins associated with the type-iii secretion systems might be involved in modification of the secreted targets, or in the stabilization of these targets prior to their secretion. For example, a distinct feature of the type-iii systems is the existence of cytoplasmic chaperones that assist in the translocation of the secreted targets by maintaining them in a conformation that is competent for export and/or by preventing their degradation ( Wattiau et al., 1996). Usually, these chaperones are encoded next to or near the gene encod- ing their cognate protein. In addition, the chaperones identified so far share certain structural features such as high charge, small size, and a potential to form a-helices. SicA (Kaniga et al., 1995b) is a protein in Salmonella that shares sequence homology with the cytoplasmic chaperones IpgC (Baudry et al., 1988) and LcrH (SycD) ( Bergman et al., 1991; Price et al., 1989) of Shigella and Yersinia, respectively. Therefore, it is most likely involved in either guiding the secreted targets to the translocation machinery or in preventing their prema- ture degradation. Mutations in sica prevented the secretion of SipA, SipB, and SipC, but not InvJ, which indicates that the function of SicA is restricted to a subset of secreted proteins ( Tucker et al., 1995). Another protein with putative chaperone function in Salmonella is InvI (Collazo et al., 1995). This protein, which is encoded immediately adjacent to invj and spao, exhibits some structural features observed in the type-iii chaper- ones such as small size, high charge and predicted potential to form a-helical structures. It is therefore possible that InvI may serve as a chaperone for the secreted proteins InvJ and SpaO. However, this hypothe- sis remains to be experimentally substantiated. IacP is a Salmonella protein that belongs to the family of acyl carrier proteins and therefore might be involved in the post-translational modification of exported proteins ( Kaniga et al., 1995a). In fact, the modification of secreted proteins has been observed in other systems. In the type-i system, for example, hemolysin requires an acyl carrier protein for its post-translational modifica The inner membrane platform Several proteins have been identified in the type-iii systems that, based on their secondary structures, are predicted to be located in the inner membrane. In Salmonella, these include the InvA (Galán et al., 1992), SpaP, SpaQ, SpaR, and SpaS proteins (Collazo and Galán, 1996; Groisman and Ochman, 1993). InvA is a polytopic inner membrane protein with two domains: an N-terminal domain with at least eight putative TM segments and a C-terminal region located in the cytoplasmic compartment (Galán et al., 1992). This topological organization has been confirmed using biochemical fractionation techniques and studies with the transposon TnphoA (Ginocchio, 1994). The structural features of InvA suggest that this protein may form a channel in the inner membrane through which the exported polypeptides are translocated. However, thus far, there is no experimental evidence to substantiate this hypothesis. The SpaP, SpaQ and SpaR proteins contain hydrophobic regions that are likely to span the membrane (Groisman and Ochman, 1993; Collazo and Galán, 1996). This observation is supported further by several studies in other systems that seem to indicate that some of the homologs of these proteins are located in the membrane. For example, protein fusion experiments using b-lactamase have indicated that the Caulobacter crescentus FliQ and FliR proteins, which are homologous to SpaQ and SpaR, are likely to be membrane associated ( Zhuang and Shapiro, 1995). In fact, SpaQ is highly hydrophobic with at least two putative TM regions which suggests that this protein could be almost completely embedded in the membrane. Studies in Yersinia pestis have indicated that the YscR protein, a homolog of SpaP, is an integral membrane protein with at least four TM spanning domains ( Fields et al., 1994). Recent studies have shown that non-polar mutations in the spa genes abolished Salmonella entry and prevented protein secretion (Collazo and Galán, 1996). Therefore, the Spa proteins may be structural components of the translocase or may assist in the translocation process Accessory proteins

4 54 C.M. Collazo, J.E. Galán / Gene 192 (1997) tion. This acylation is essential for the activation of this tional categories of secreted targets. One sub-class of toxin and for its proper insertion into the plasma proteins plays an important role in protein secretion membrane of the mammalian cell (Braun et al., 1993). and the others are candidates to be effector molecules It is possible that IacP modifies some important component of the invasion-associated secretion pathway that (Collazo and Galán, 1996). or to be involved in their delivery into the host cell is targeted to the host-cell membrane. However, the target(s) that might be lipidated by IacP has not been 4.1. Targets involved in secretion identified thus far. InvH is involved in the ability of Salmonella to attach Two secreted proteins, InvJ and SpaO, are absolutely to and invade cultured epithelial cells (Altmeyer et al., required for protein secretion through the type-iii 1993). Fractionation studies indicate that this protein system (Collazo and Galán, 1996). Introduction of localizes to the membrane fraction. Mutations in the mutations in their coding genes completely abolished gene encoding this protein had a more pronounced effect the secretion of all targets of the secretion apparatus in the host-adapted strains S. gallinarum, S. choleraesuis including the Sip proteins (see below) (Collazo and and S. typhimurium. Therefore, InvH might be an Galán, 1996). However, mutations in the sip genes did adhesin that plays a role in the initial interactions of not prevent the secretion of InvJ, SpaO or other Sip Salmonella with the mammalian cell before the internalproteins ( Kaniga et al., 1995a). These observations ization process is initiated. suggest that there is a hierarchy in the secretion process and that a subset of exported targets is essential for the 3.5. Other determinants associated with the type-iii translocation of another class of secreted proteins. It is secretion system unknown whether this is a general phenomenon that exists in other type-iii systems or whether this is specific Other proteins such as InvE (Ginocchio et al., 1992) for Salmonella. InvJ and SpaO are encoded in the and OrgA (Jones and Falkow, 1994) are involved in vicinity of the highly conserved inv/spa loci (Collazo Salmonella entry and, possibly, in protein secretion. and Galán, 1996; Collazo et al., 1995; Groisman and Indeed, InvE has been shown to play a role in both Ochman, 1993; Li et al., 1995). However, these proteins processes. Although inve mutants grown under in vitro share little or no similarity to their cognate proteins in conditions are defective in protein secretion (M. Suárez other microorganisms, which suggests that they may be and J.E.G., unpublished observations), they are able to involved in functions that are specific for Salmonella. secrete InvJ upon exposure to cultured epithelial cells Another protein that plays a role in the secretion (see below) ( Zierler and Galán, 1995). These observaprocess is SipD which is homologous to the Shigella tions suggest an important role for InvE in regulating IpaD protein ( Kaniga et al., 1995a). Mutations in sipd, the secretion process. Consistent with a regulatory role and to a lesser extent in sipb, led to increased secretion for InvE is its homology to YopN (LcrE) of Yersinia of a subset of targets of the inv/spa translocon (Kaniga (Forsberg et al., 1991; Viitanen et al., 1990), a protein et al., 1995a,b). This is similar to the phenotype of that has been suggested to be involved in the regulation mutations in the Shigella ipab and ipad genes (Ménard of Yop secretion. et al., 1994; Parsot et al., 1995). How SipB and SipD Another determinant involved in Salmonella entry is modulate the secretion process is unknown. In Shigella, encoded by orga, a gene shown to be oxygen-regulated the IpaB and IpaD proteins are associated with the (Jones and Falkow, 1994). OrgA shares significant membrane and it has been speculated that they may sequence homology with MxiK (Allaoui et al., 1992), a block the secretion apparatus by forming a plug or lid protein of Shigella involved in the secretion of the Ipa (Ménard et al., 1994). However, if the Salmonella homoinvasins. Although the exact role of OrgA in protein logs are involved in a similar function, the blockage of translocation has not been determined, its homology to secretion can not apply to all targets since the secretion MxiK predicts a similar function. levels of InvJ were not affected in a sipd mutant. 4. Targets of the type-iii secretory system in Salmonella 4.2. Targets with putative effector functions in the host cell Several proteins in the range of kda that use the type-iii secretory machinery to exit the bacterial cell The SipA ( Kaniga et al., 1995a), SipB and SipC have been identified in Salmonella ( Kaniga et al., 1995b; ( Kaniga et al., 1995b) proteins are homologous to the Pegues et al., 1995). These include the InvJ (Collazo IpaA, IpaB and IpaC ( Hale, 1991) proteins of Shigella, et al., 1995), SpaO (Li et al., 1995; Collazo and Galán, respectively. Although it is known that SipB and SipC 1996), SptP ( Kaniga et al., 1996) and Sip proteins ( Kaniga et al., 1995b), but not SipA ( Kaniga et al., (Kaniga et al., 1995a,b). There are at least two func- 1995a), are required for the internalization of Salmonella

5 C.M. Collazo, J.E. Galán / Gene 192 (1997) into cultured epithelial cells, a specific function has not are regions of specificity that are located in the C-termini been ascertained for these proteins. of these proteins. Based on sequence analysis, it has been suggested that Additionally, the secretory machinery is capable of IpaB may be a pore-forming protein (High et al., 1992). exporting heterologous proteins. For example, the IpaB IpaB, SipB and the Yersinia protein YopB ( Hakansson protein of Shigella was secreted in Yersinia pseudotuberculosis et al., 1993) share significant sequence homology (65% and the YopE protein of Yersinia was transloet identity) in a hydrophobic domain related to the RTX cated by S. typhimurium via the Inv-secretory machinery family of pore-forming toxins. However, no pore-forming ( Rosqvist et al., 1995). Secretion required the presence activity has been formally demonstrated in any of of the cognate chaperones for both proteins. these proteins. Alternatively, these proteins might be Furthermore, in addition to heterologous secretion, involved in delivering another molecule(s) into the host functional complementation has also been observed cell or, their pore-forming activity per se could be among secreted targets of Salmonella and Shigella responsible for triggering a signal transduction pathway ( Hermant et al., 1995). A Shigella ipab mutant strain by inducing ion fluxes in the infected cell. was complemented by a plasmid carrying the sipb gene Recently, a new target protein of the type-iii secretory and its corresponding chaperone. These results suggest system has been identified in Salmonella. This protein, that SipB was probably exported in Shigella and that which has been termed SptP, has a modular architecture these two proteins may be functional homologs. and consists of two domains ( Kaniga et al., 1996). One domain, located at the N-terminus, shares sequence homology with the exotoxin S of Pseudomonas aerugi- 6. Regulation of the secretion process nosa and the YopE protein of Yersinia spp. The other domain, located at the C-terminal end, is homologous The secretion process, and in turn the associated to the catalytic domain of tyrosine phosphatases, including phenotypes, are regulated at both the transcriptional that of the Yersinia YopH protein. Consistent with and post-transcriptional levels. Several factors such as this latter homology, SptP has been shown to have growth phase (Lee and Falkow, 1990), oxygen tension tyrosine phosphatase activity in biochemical assays ( Ernst et al., 1990; Lee and Falkow, 1990), and osmolarity ( Kaniga et al., 1996). This activity was abolished when (Galán and Curtiss, 1990) affect the ability of an essential cysteine residue present in the catalytic site Salmonella to enter epithelial cells as well as the expression of the tyrosine phosphatase was substituted by a serine. of the invasion genes. Although the molecular A non-polar mutation in sptp did not prevent Salmonella mechanisms of this type of regulation are not completely from entering epithelial cells or macrophages. However, understood, changes in the degree of DNA supercoiling animal studies have shown that SptP is required for are likely to be involved (Galán and Curtiss, 1990). virulence since sptp mutants were defective in the colonization In addition, at least two regulatory proteins associated of the spleens of orally infected mice. 5. Functional conservation of heterologous type-iii secretion systems with the invasion phenotype, InvF and HilA, have been identified in the centisome 63 region of the Salmonella chromosome. InvF is a member of the AraC family of transcriptional activators ( Kaniga et al., 1994). Although this gene is clearly essential for bacterial entry, its regulatory target(s) has not been identified. HilA is a member of the OmpR/ToxR family of transcriptional Several animal and plant pathogens have devised similar strategies for the export of virulence determinants activators (Miras et al., 1995; Bajaj et al., 1995). Like ( Van Gijsegem et al., 1993). The structural components InvF, this protein is also required for bacterial internalof these systems are highly conserved at the protein ization. Some of the regulatory targets of HilA are orga, sequence level (Table 1). In addition, heterologous complementation sipc and invf (Bajaj et al., 1995). These findings suggest among components from different species a complex regulatory loop in which a protein conceiva- has been observed. A non-invasive Salmonella spap bly involved in regulation (InvF ) is under the control mutant was complemented by the Shigella spa24 gene of another regulator ( HilA). The secretion apparatus (Groisman and Ochman, 1993). In addition, a more and the invasion phenotype are also regulated by more detailed study has shown that although the Shigella global regulatory networks such as those that control mxia gene was able to complement a non-invasive intracellular survival (PhoP/PhoQ) (Behlau and Miller, inva mutant, the lcrd gene of Yersinia was unable to 1993; Pegues et al., 1995), or flagellar assembly complement this mutant (Ginocchio and Galán, ( Eichelberg et al., 1995). 1995). However, a chimeric protein consisting of the In addition to the transcriptional regulatory mechanisms, N-terminus of LcrD and the C-terminus of InvA was the function of the secretion apparatus is regu- able to restore the ability of the inva mutant to enter lated by other events that do not require de novo gene cultured epithelial cells. These results indicate that there expression or protein synthesis (Macbeth and Lee, 1993;

6 56 C.M. Collazo, J.E. Galán / Gene 192 (1997) Table 1 Components of the S. typhimurium type-iii secretion system with homologues in one or more bacterial pathogensa Salmonella spp. Shigella spp. Yersinia spp. P. solanacearum P. syringae X. campestris Flagellar assembly Localizationb InvA MxiA LcrD HrpO HrpI HrpC2 FlhA inner membrane SpaP Spa24 YscR HrpT HrpW ORF2 FliP inner membrane SpaQ Spa9 YscS HrpU HrpO FliQ inner membrane SpaR Spa29 YscT HrpC HrpX HrpB8 FliR inner membrane SpaS Spa40 YscU HrpN HrpY FlhB inner membrane InvG MxiD YscC HrpA HrpH HrpA1 outer membrane PrgH MxiG outer membrane PrgK MxiJ YscJ HrpI HrpC HrpB3 FliF outer membrane InvE MxiC LcrE/YopN unknown InvB Spa15 FliH unknown InvC Spa47 YscN HrpE HrpJ4 HrpB6 FliI unknown SpaO Spa33 YscQ HrpQ HrpU FliN/FliY extracellular IagB IpgF unknown PrgI MxiH YscF unknown PrgJ MxiI unknown OrgA MxiK unknown SicA IpgC SycD/LcrH cytoplasmic IacP OrfX unknown asearches were conducted at the NCBI server using the Blast program. Sequences were from GenBank release blocalization based on experimental data obtained for at least one member of the family. 7. Mechanisms of Salmonella and Shigella interactions with host cells: how different are they? Ginocchio et al., 1994; Zierler and Galán, 1995). This regulatory network is manifested by the rapid stimulation of the type-iii secretion system upon bacterial contact with host cells (Ginocchio et al., 1994; Zierler and Galán, 1995). Studies have shown that InvJ secretion is stimulated when Salmonella is exposed to cultured epithelial cells, and, to a lesser extent, upon bacterial contact with culture dishes coated with serum ( Zierler and Galán, 1995). Indeed, the contact-induced InvJ secretion was dependent on an intact type-iii secretion system since mutations in the invc and invg genes prevented the contact-stimulated secretion of this protein. These observations implicate an essential role for the secretion apparatus upon Salmonella exposure to mammalian cells. Furthermore, another consequence of the interaction of Salmonella with host cells is the assembly of appendage-like organelles called invasomes on the bacterial surface (Ginocchio et al., 1994). These structures are transient and have a very short half-life. The inv locus encoding the type-iii secretory system has been shown to be required for the assembly of these structures since invc and invg mutants prevented their formation. In analogy to Salmonella, Shigella form organized structures consisting of extended sheets when grown under certain inducing conditions (Parsot et al., 1995). Some of the Ipa proteins are components of these filamentous structures. It is possible that the extended sheets observed in Shigella may be related to the invasomes identified in Salmonella. The correlation between protein secretion and invasome assembly needs to be understood at the molecular level. The remarkable similarities between the molecular genetic bases of Salmonella and Shigella interactions with host cells are surprising considering the pathophysi- ological differences between the diseases caused by these two microorganisms ( Hook, 1990; Sansonetti, 1992). Studies on the interaction of these pathogens with their host cells have also revealed significant differences. For example, although both pathogens enter cells via a membrane ruffling-mediated mechanism, it is clear that differences must exist in the signal transduction path- ways induced by these microorganisms since in contrast to Salmonella, Shigella does not cause calcium ion fluxes during internalization (Pace et al., 1993; Clerc et al., 1989). Furthermore, whereas Salmonella can enter epi- thelial cells through the apical surface ( Finlay et al., 1988), Shigella can only access these cells through the basolateral side ( Mounier et al., 1992). In addition, the fate of each pathogen once inside the mammalian cell is different. Salmonella spp. remain enclosed in an endocytic vesicle and transcytose to the basolateral pole of the epithelial cell ( Takeuchi, 1967; Takeuchi and Sprinz, 1967). In contrast, Shigella spp. lyse the endocytic vacuole and gain access to the cytoplasmic compartment, whereupon they spread to neighboring cells (Sansonetti et al., 1986; Ogawa et al., 1968). What are the molecular genetic bases for these phenotypic differences? Some of these differences may arise from the development of different strategies for sensing

7 C.M. Collazo, J.E. Galán / Gene 192 (1997) or timing the activation of the invasion-associated secre- by which these putative signaling proteins exert their tion apparatus. Other differences may arise from the function will also be the focus of intense research in the effector molecules themselves. For example, although coming years. SipB and IpaB share 65% identity in a domain which Type-III secretory pathways have been identified in contains a putative membrane spanning region, the other animal and plant pathogens. Therefore, understanding overall sequence identity between these two proteins is the molecular mechanisms of these complex only 28% ( Kaniga et al., 1995b). Other Sip and Ipa secretory machineries could help to gain insights into proteins are even more divergent at the protein sequence the pathogenesis of all of these microorganisms as well level. This is the case for the SipA and IpaA proteins, as to learn more about other basic processes such as where the overall sequence identity is only 25% ( Kaniga protein secretion, sensing and transmission of environ- et al., 1995a). Alternatively, the Shigella and Salmonella mental signals and the assembly of supramolecular type-iii secretion systems may have different targets. structures. This in turn will provide new knowledge for For example, as mentioned previously, a secreted tyro- the development of novel therapeutic strategies for this sine phosphatase with no apparent homolog in Shigella group of bacterial pathogens. has been recently identified in Salmonella ( Kaniga et al., 1996). If this is a Salmonella-specific determinant it may help to explain some of the phenotypic differences Acknowledgement between these two microorganisms. We would like to thank Stephanie C. Tucker for critical review of the manuscript and Wolf-Dietrich 8. Another type-iii secretory system in Salmonella? Hardt for critical review of the manuscript and the generous gift of Fig. 1. Work in the laboratory is sup- Several putative components of a type-iii secretory ported by Grants from the National Institutes of Health, system have been recently identified in a region outside the Pew Charitable Trust and the American Heart of centisome 63 ( Hensel et al., 1995). Although this Association. putative secretory system has not been fully characterized, it probably does not encode redundant functions since this would have precluded phenotypic observations References of mutations of the components of the type-iii secretory system encoded at centisome 63. However, it is still Allaoui, A., Sansonetti, P.J. and Parsot, C. (1992) MxiJ, a lipoprotein possible that this novel secretion system may be funca involved in secretion of Shigella Ipa invasins, is homologous to YscJ, tional only under certain physiological conditions and secretion factor of the Yersinia Yop proteins. J. Bacteriol. 174, some of the components may therefore exert redundant Allaoui, A., Menard, R., Sansonetti, P. and Parsot, C. (1993) Characfunctions. The interplay between these two systems and terization of the Shigella flexneri ipgd and ipgf genes, which are their function in the pathogenic cycle of Salmonella located in the proximal part of the mxi locus. Infect. Immun. 61, remains to be investigated Allaoui, A., Sansonetti, P.J., Menard, R., Barzu, S., Mounier, J., Phalipon, A. and Parsot, C. (1995) MxiG, a membrane protein required 9. Conclusions for secretion of Shigella Ipa invasins: involvement in entry into epithelial cells and in intercellular dissemination. Mol. Microbiol. 17, The requirement for a specialized protein secretion Altmeyer, R.M., McNern, J.K., Bossio, J.C., Rosenshine, I., Finlay, system helps explain the genetic complexity of the invaof B.B. and Galán, J.E. (1993) Cloning and molecular characterization a gene involved in Salmonella adherence and invasion of cultured sion phenotype of Salmonella spp. This protein secretion epithelial cells. Mol. Microbiol. 7, system, termed type-iii or contact-dependent, is at the Arlat, M., Van Gijsegem, F., Pernollet, J.C. and Boucher, C.A. (1994) center of the two-way biochemical interaction between PopA1, a protein which induces a hypersensitivity-like response on the bacteria and the host cell that leads to bacterial specific petunia genotypes, is secreted via the Hrp pathway of Pseu- internalization and other host-cell responses. Most of domonas solanacearum. EMBO J. 13, the components and many of the targets of this protein Bajaj, V., Hwang, C. and Lee, C.A. (1995) hila is a novel ompr/toxr family member that activates the expression of Salmonella typhimusecretion apparatus have been identified. The remaining rium invasion genes. Mol. Microbiol. 18, challenge for the future is to understand how this Baudry, B., Kaczorek, M. and Sansonetti, P.J. (1988) Nucleotide apparatus is activated upon contact with the host cells sequence of the invasion plasmid antigen B and C genes (ipab and and how the target proteins are secreted and/or translo- ipac) of Shigella flexneri. Microb. Pathogen. 4, cated into the host cell. Although many proteins that Behlau, I. and Miller, S.J. (1993) A Pho-P-repressed gene promotes Salmonella typhimurium invasion of epithelial cells. J. Bacteriol. 175, utilize this protein secretion system to exit the bacterial cell have been identified, our understanding of their Bergman, T., Hakansson, S., Forsberg, A., Norlander, L., Macellaro, function is limited. The investigation of the mechanisms A., Baeckman, A., Boelin, I. and Wolf-Watz, H. (1991) Analysis of

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Immun. 57, invasion of host epithelial cells by Salmonella typhimurium and Shi- Collazo, C.M. and Galán, J.E. (1996) Requirement for exported pro- gella flexneri. EMBO J. 12, teins in secretion through the invasion-associated type-iii system of Hakansson, S., Bergman, T., Vanooteghem, J.C., Cornelis, G. and Salmonella typhimurium. Infect. Immun. 64, Wolf-Watz, H. (1993) YopB and YobD constitute a novel class of Collazo, C.M., Zierler, M.K. and Galán, J.E. (1995) Functional analy- Yersinia Yop proteins. Infect. Immun. 61, sis of the Salmonella typhimurium invasion genes invi and invj and Hale, T.L. (1991) Genetic basis of virulence in Shigella species. Microidentification of a target of the protein secretion apparatus encoded biol. Rev. 55, in the inv locus. Mol. Microbiol. 15, He, S.Y., Huang, H.-C. and Collmer, A. (1993) Pseudomonas syringae Donnenberg, M.S., Yu, J. and Kaper, J.B. 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(1995) Caulobacter FliQ and FliR Functional conservation of the secretion and translocation membrane proteins, required for flagellar biogenesis and cell division, machinery for virulence proteins of versiniae, salmonellae and shigellae. belong to a family of virulence factor export proteins. J. Bactemachinery EMBO J. 14, riol. 177, Russel, M. (1995) Moving through the membrane with filamentous Zierler, M. and Galán, J.E. (1995) Contact with cultured epithelial phages. Trends Microbiol. 3, cells induces the secretion of the Salmonella typhimurium invasion Salmond, G.P.C. and Reeves, P.J. (1993) Membrane traffic wardens protein InvJ. Infect. Immun. 63,

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