Download Import of bacterial pathogenicity factors into mitochondria

Available online at www.sciencedirect.com
Import of bacterial pathogenicity factors into mitochondria
Vera Kozjak-Pavlovic, Katharina Ross and Thomas Rudel
Recent research on the mechanism underlying the interaction
of bacterial pathogens with their host has shifted the focus to
secreted microbial proteins affecting the physiology and innate
immune response of the target cell. These proteins either
traverse the plasma membrane via specific entry pathways
involving host cell receptors or are directly injected via bacterial
secretion systems into the host cell, where they frequently
target mitochondria. The import routes of bacterial proteins are
mostly unknown, whereas the effect of mitochondrial targeting
by these proteins has been investigated in detail. For a number
of them, classical leader sequences recognized by the
mitochondrial protein import machinery have been identified.
Bacterial outer membrane b-barrel proteins can also be
recognized and imported by mitochondrial transporters.
Besides an obvious importance in pathogenicity,
understanding import of bacterial proteins into mitochondria
has a highly relevant evolutionary aspect, considering the
endosymbiotic, proteobacterial origin of mitochondria. The
review covers the current knowledge on the mitochondrial
targeting and import of bacterial pathogenicity factors.
Addresses
Max Planck Institute for Infection Biology, Department of Molecular
Biology, Research Group for Molecular Infection and Cancer Biology,
Charitéplatz 1, D-10117 Berlin, Germany
Corresponding author: Kozjak-Pavlovic, Vera ([email protected]), Ross, Katharina ([email protected]) and Rudel,
Thomas ([email protected])
Current Opinion in Microbiology 2008, 11:9–14
This review comes from a themed issue on
Bacteria
Edited by Thomas Meyer and Ilan Rosenshine
Available online 14th February 2008
1369-5274/$ – see front matter
# 2008 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.mib.2007.12.004
Introduction
It is generally accepted that mitochondria have arisen
from an endosymbiotic alpha-proteobacterial ancestor
[1,2]. This fact is reflected in the protein content of
mitochondria, many of mitochondrial proteins having
counterparts in modern-day bacteria [3]. During the
establishment of endosymbiosis, mitochondria have
transferred the information for the majority of their
proteins to the host cell nucleus. As a consequence,
the import of nuclear-encoded proteins into mitochondria
www.sciencedirect.com
made necessary the development of protein import
machines. It is possible that one process was accelerated
by the other, or that both processes happened simultaneously.
Mitochondria have been identified as the target of an
increasing number of bacterial proteins, which are transferred to the cell during infection, a process that often
plays a crucial role in bacterial pathogenicity [4]. Consistent with a central role of mitochondria in apoptosis
regulation [5], nearly all identified bacterial proteins
targeting mitochondria modulate host cell death. They
frequently induce the release of pro-apoptotic factors like
cytochrome c and cause a breakdown of the mitochondrial
membrane potential (DCm). Less is known about cell
entry route and mitochondrial import, whereas mitochondrial phenotypes caused by bacterial effectors are well
investigated.
Multiple traits indicate parallels between bacterial and
mitochondrial protein transport systems. For example, a
peptidase from Rickettsia prowazekii with structural
homology to mitochondrial processing peptidase
(MPP) can cleave MPP substrates, the authentic signal
sequences of proteins targeting mitochondria [6].
Additionally, certain bacterial signal peptides are recognized by mitochondrial import receptors and mediate
protein transport into mitochondria [7]. Moreover, bacterial pathogenicity factors have been shown to contain
N-terminal mitochondrial targeting signals [8,9] capable
of directing to mitochondria any protein fused to it.
Bacterial porins can also be targeted to host mitochondria [10–12]. They assume b-barrel topology and are
therefore similar to mitochondrial porin, or voltage-dependent anion-regulated channel (VDAC). Remarkably,
b-barrel proteins are found exclusively in outer membranes of bacteria, mitochondria, and chloroplasts,
pointing to a common evolutionary origin of this protein
class. Besides proteins with N-terminal mitochondrial
presequence or b-barrel structure, a heterogeneous class
of bacterial proteins including many bacterial toxins
target mitochondria by so far unknown import routes
[13–20].
Here, we will summarize the current view on the mitochondrial targeting and import of an emerging class of
bacterial pathogenicity factors.
Protein import into mitochondria
Protein import machines of mitochondria are complex
and differ between organisms, though a core of each
machine seems to be present in all eukaryotes [21].
Current Opinion in Microbiology 2008, 11:9–14
10 Bacteria
Figure 1
Import and sorting pathways of proteins in mammalian mitochondria. Proteins enter the mitochondrial intermembrane space via the translocase of the
outer membrane (TOM) complex. The sorting and assembly machinery (SAM) complex mediates membrane insertion of b-barrel proteins. Proteins
are sorted to the inner membrane by the translocase of the inner mitochondrial membrane (TIM) complexes TIM22 and TIM23. Proteins interacting with
the TIM complexes are either integrated into the inner mitochondrial membrane or transported into the mitochondrial matrix.
Most of the components have been first described and
functionally studied in fungal systems, to be later identified in mammals [22]. In the outer membrane, practically
all proteins are first recognized by the translocase of the
outer mitochondrial membrane (TOM) complex, which
consists of the core component Tom40, receptors Tom20,
Tom22, and Tom70, and various numbers of small Tom
proteins (Figure 1). Proteins are afterwards transferred
either to the TIM complexes in the inner mitochondrial
membrane or to the SAM/TOB complex in the outer
mitochondrial membrane. The TIM23 complex, with the
PAM complex, is responsible for the import of proteins
containing an N-terminal presequence, which are usually
matrix or inner-membrane proteins. Preproteins are processed by the MPP. The TIM22 complex is necessary for
the membrane integration of proteins that contain
internal targeting signals, as are carrier proteins of the
inner mitochondrial membrane. The SAM/TOB complex, with Sam50 as the central component, facilitates
membrane integration of b-barrel proteins [23–25].
Recently, metaxins have also been identified as functioning with Sam50 during integration of b-barrel proteins in
mammalian mitochondria, though they probably exist in a
protein complex separate from Sam50 [26].
The only one of these complexes with a bacterial counterpart is the SAM complex. Its core component, Sam50,
shares sequence homology with Omp85, a protein of the
Current Opinion in Microbiology 2008, 11:9–14
outer membrane of Neisseria sp. Similar to Sam50 in
mitochondria, Omp85 facilitates the integration of neisserial porins into the outer bacterial membrane [27].
Omp85 homologs have since been identified in other
bacteria, as well as in mitochondria and chloroplasts of
all other organisms [28–30]. However, the main entry
point of practically all proteins into mitochondria, the
TOM complex, has no homologous machinery in bacteria
[21].
Bacterial proteins with N-terminal
mitochondrial targeting sequence
Mitochondrial-associated protein (Map, former Orf19)
and EspF from enteropathogenic E. coli (EPEC) are
the best studied bacterial proteins that possess an Nterminal mitochondrial presequence with putative cleavage signal. Both proteins are injected into host cells via
the type 3 secretion system (TTSS) and colocalize with
host mitochondria [8,9,31].
Mitochondria-associated Map causes the dissipation of
DCm and mitochondrial fragmentation, but appears to be
dispensable for EPEC-induced host cell apoptosis
[8,31]. A smaller form of Map can be found, possibly
representing a mitochondrial imported form cleaved by
the host MPP [8]. In vitro import assays with mitochondria
from temperature-sensitive yeast mutants have shown
that Map import depends on Tom22, Tom40, and
www.sciencedirect.com
Bacterial proteins imported into mitochondria Kozjak-Pavlovic, Ross and Rudel 11
mtHsp70. Moreover, import of Map requires an intact
DCm, typical for proteins imported into the mitochondrial
matrix via the TIM23 complex [31]. It is not known
whether homologs of Map, EPEC TrcA/TrcP and Shigella IpgB, have similar characteristics [8].
EPEC EspF has also a canonical N-terminal mitochondrial targeting signal and, upon infection, localizes to
these organelles. EspF triggers apoptosis during EPEC
infection by dissipating DCm, causing cytochrome c
release and activating caspases 9 and 3. The N-terminal
34 amino acids of EspF fused to eGFP are sufficient to
guide this construct to mitochondria. As for Map, a
smaller form of EspF, possibly cleaved by the host
MPP, can be detected in infected cells [9]. Recently,
Nagai et al. demonstrated that the loss of DCm inhibited
the mitochondrial import of EspF, suggesting a role of
the inner membrane translocation machinery [32].
Results from our group indicate that EspFu, an EspF
homologue from enterohaemorrhagic E. coli (EHEC),
contains an N-terminal mitochondrial targeting
sequence, which guides its translocation to mitochondria
upon overexpression (V.K.-P., John Leong, T.R., unpublished data).
Mitochondria-targeted bacterial proteins with
b-barrel structure
Neisserial PorB proteins and Omp38 from Acinetobacter
baumannii belong to this group [4,10–12]. These proteins
are not secreted by classical bacterial secretion systems
and the details of how they reach the host cell mitochondria during infection are still unknown. Omp38 of A.
baumannii is shown to be targeted to mitochondria of
Hep2 cells, where it induces the release of cytochrome c
and apoptosis inducing factor (AIF), promoting apoptosis
[12]. How Omp38 is recognized and taken up by mitochondria has not been investigated. The import of PorB
from Neisseria gonorrhoeae has been studied in yeast mitochondria, where it was shown that this protein follows the
import pathway similar to that of VDAC, being recognized by Tom20 and transported through the Tom40 pore
[33]. In the light of the SAM complex discovery, it
remains to be determined whether Sam50, a homolog
of neisserial Omp85, plays a role in mitochondrial import
of PorB. Gonococcal PorB expressed in human cells
localizes to mitochondria and causes the dissipation of
DCm, but not the release of cytochrome c. The previously
determined outer membrane localization, however, does
not explain the decoupling effect of PorB, leaving the
possibility that some of the PorB molecules spontaneously integrate into the inner mitochondrial membrane where they dissipate DCm.
Proteins that do not belong to either category
This large group of proteins consists mainly of bacterial
toxins, which are secreted by the bacteria and enter the
host cell by endocytosis. Two exceptions are the EPECwww.sciencedirect.com
translocated intimin receptor (Tir) and Salmonella SipB
that are both injected into the host cell by TTSS. Host
cell-associated Tir functions as a receptor for bacterial
adherence. In an overexpression study, Tir, C-terminally
tagged with YFP, colocalized with mitochondria and
induced apoptosis. It remains to be shown whether Tir
associates with host mitochondria during infection [34].
Salmonella enterica SipB targets host mitochondria during
infection and supports autophagy-mediated cell death in
caspase-1-deficient macrophages [17]. Transiently overexpressed SipB induces the formation of multivesicular
fusion structures that contain marker proteins of endoplasmic reticulum and mitochondria. Although no known
mitochondrial targeting sequence can be found, SipB
seems to specifically target mitochondria, as also a mutant
that has no fusogenic activity localizes to mitochondria
[17].
Among the bacterial toxins associating with mitochondria,
the vacuolating cytotoxin (VacA) from Helicobacter pylori
has been extensively studied. Both purified and overexpressed VacA localized to mitochondria of mammalian
cells and induced the loss of DCm and the release of
cytochrome c [13,35]. Radiolabeled VacA was shown to be
rapidly imported over the mitochondrial outer membrane,
though it seems to lack a mitochondrial targeting
sequence [13]. Cytotoxic activity of VacA may come from
its tendency to form anion-selective channels in mitochondrial membranes [35]. However, in another report,
VacA was found in late endosomes and it was demonstrated that H. pylori-induced cytotoxicity does not
require a direct contact between VacA and mitochondria
[36].
A range of other apoptosis-inducing toxins associate with
host mitochondria if applied in purified form to host cells,
inducing DCm dissipation and cytochrome c release.
These include the Staphylococcus aureus a-toxin [15],
the S. aureus Panton-Valentine leukocidin (PVL) [18],
the Streptococcus pneumoniae pneumolysin [20], the Clostridium difficile Toxin A [14] and Toxin B [19], and the
Clostridium sordellii Lethal toxin [16]. All these toxins
added in purified form damage isolated mitochondria by
unknown mechanisms. Considering this large group and
the little mechanistic insight we have, the importance of
the toxin–mitochondria association has clearly been
underestimated in the past.
Conclusions
Bacterial proteins targeting mitochondria comprise an
emerging group of pathogenicity factors involved in the
regulation of host cell death. The few examples investigated in detail unveiled an involvement of mitochondrial
import machines in their uptake (Figure 2). Several
proteins for inner-membrane transport and outer-membrane assembly (Sam50) have structural and functional
bacterial counterparts, opening the possibility of a coCurrent Opinion in Microbiology 2008, 11:9–14
12 Bacteria
Figure 2
Import of bacterial proteins into mitochondria. EPEC proteins EspF and Map enter mitochondria via the TOM complex and are subsequently sorted to
the mitochondrial matrix. Uptake of PorB from N. gonorrhoeae by mitochondria requires the TOM complex. Consistent with the b-barrel topology,
PorB may integrate into the outer membrane. A localization to the mitochondrial inner membrane would be consistent with the strong uncoupling
activity observed for PorB. The entry routes for VacA from H. pylori and Omp38 from A. baumannii are until date unknown.
evolution of mitochondria-targeted bacterial effectors and
mitochondrial import. Import studies were mostly performed on isolated yeast mitochondria, a model system
that leaves much to be desired, considering that most of
the pathogenic bacteria in question infect only mammalian cells. Clearly, the import routes for most of the
mitochondria-associated bacterial proteins are unknown
and have to be investigated in relevant systems in future.
The latter are mitochondria of the respective host
cells, which are now generally accessible for import
experiments by applying the new technology of RNA
interference for specific loss of function studies [26].
Table 1
Bacterial pathogenicity factors targeting mitochondria
Bacterial protein
Organism
EspF
Map
EPEC
EPEC
Tir
SipB
PorB
EPEC
Salmonella
N. gonorrhoeae
PorB
Omp38
VacA
a-Toxin
PVL
N. meningitidis
A. baumanii
H. pylori
S. aureus
S. aureus
Pneumolysin
Lethal toxin
Toxin A
Toxin B
S. pneumoniae
C. sordelli
C. difficile
C. difficile
Mitochondrial phenotype
Biological effect
Targeting signal/Required
mitochondrial
import proteins
Loss of DCm
Mitochondrial fragmentation,
loss of DCm
Unknown
Membrane fusion
Release of cytochrome c,
loss of DCm
Protection from DCm loss
Release of cytochrome c, AIF
Release of cytochrome c
Release of cytochrome c
Release of cytochrome c,
Smac/DIABLO
Release of AIF
Release of cytochrome c
Release of cytochrome c
Swelling, release of cytochrome c
Induction of apoptosis
Unknown
[9,32]
[8,31]
Induction of apoptosis
Induction of autophagy
Induction of apoptosis
N-terminal leader/n.d.
N-terminal leader/Tom40,
Hsp70
Unknown
Unknown
b-Barrel protein/Tom20, Tom40
Inhibition of apoptosis
Induction of apoptosis
Induction of apoptosis
Induction of apoptosis
Induction of apoptosis
b-Barrel protein/n.d.
b-Barrel protein/n.d.
Unknown/n.d.
b-Barrel protein/n.d.
Unknown/n.d.
[10]
[12]
[13]
[15]
[18]
Induction
Induction
Induction
Induction
Unknown/n.d.
Unknown/n.d.
Unknown/n.d.
Unknown/n.d.
[20]
[16]
[14]
[19]
Current Opinion in Microbiology 2008, 11:9–14
of
of
of
of
cell death
apoptosis
apoptosis
apoptosis
References
[34]
[17]
[11,33]
www.sciencedirect.com
Bacterial proteins imported into mitochondria Kozjak-Pavlovic, Ross and Rudel 13
In silico analyses supported by limited experimental evidence predicted a large number of mitochondria-targeting
bacterial proteins [37]. Among these, bacterial pathogenicity factors may constitute a coherent group of proteins
involved in the cross-talk between host and pathogen,
awaiting their detection also in other bacteria. Such
proteins may be identified in phenotypic screens. For
example, a connection was established between chlamydial infection and mitochondria in a recent cytotoxicity
screen in yeast. One of the proteins significantly impairing
yeast growth was shown to target mitochondria [38].
So far, nearly all bacterial proteins identified to target
mitochondria appear to play a role in apoptosis regulation
(see Table 1). However, the few examples which could
not be linked to cell death regulation indicate that there
may be a broader function in pathogenicity, still to be
discovered. For instance, several of the mitochondriatargeting bacterial proteins like Tir, Map, and EspF also
interact with cytosolic host signaling factors involved in
cytoskeleton regulation. Cytosolic depletion of such factors by mitochondrial import may influence their function
on the host cell cytoskeleton. Modulation of the mitochondrial physiology by bacterial proteins, for example, to
adjust the host cell to metabolite or energy source
requirements of the pathogen is another possibility.
The later assumption may be supported by a recent
genome-wide RNA interference screen performed to
identify host factors that, when depleted, inhibit the
infection with the obligate intracellular bacterium Chlamydia caviae. Of these, members of TIM and TOM
import machines were identified as necessary for C. caviae
infection [39]. The specific chlamydial protein responsible for this effect remains to be identified. It is therefore
a safe assumption that bacterial pathogens and host
mitochondria as their distant relatives are still communicating in a much closer way than previously anticipated.
Acknowledgement
We thank Dr Joachim Rassow for helpful comments on the manuscript.
References and recommended reading
Papers of particular interest, published within the annual period of
review, have been highlighted as:
of special interest
of outstanding interest
1.
Gray MW, Burger G, Lang BF: Mitochondrial evolution. Science
1999, 283:1476-1481.
2.
Embley TM, Martin W: Eukaryotic evolution, changes and
challenges. Nature 2006, 440:623-630.
3.
Gabaldon T, Huynen MA: From endosymbiont to hostcontrolled organelle: the hijacking of mitochondrial protein
synthesis and metabolism. PLoS Comput Biol 2007, 3:e219.
4.
Boya P, Roques B, Kroemer G: New EMBO members’ review:
viral and bacterial proteins regulating apoptosis at the
mitochondrial level. EMBO J 2001, 20:4325-4331.
5.
Kroemer G, Galluzzi L, Brenner C: Mitochondrial membrane
permeabilization in cell death. Physiol Rev 2007, 87:99-163.
www.sciencedirect.com
6.
Kitada S, Uchiyama T, Funatsu T, Kitada Y, Ogishima T, Ito A: A
protein from a parasitic microorganism, Rickettsia prowazekii,
can cleave the signal sequences of proteins targeting
mitochondria. J Bacteriol 2007, 189:844-850.
7.
Mukhopadhyay A, Ni L, Yang CS, Weiner H: Bacterial signal
peptide recognizes HeLa cell mitochondrial import receptors
and functions as a mitochondrial leader sequence. Cell Mol Life
Sci 2005, 62:1890-1899.
8.
Kenny B, Jepson M: Targeting of an enteropathogenic
Escherichia coli (EPEC) effector protein to host mitochondria.
Cell Microbiol 2000, 2:579-590.
9.
Nougayrede JP, Donnenberg MS: Enteropathogenic
Escherichia coli EspF is targeted to mitochondria and is
required to initiate the mitochondrial death pathway. Cell
Microbiol 2004, 6:1097-1111.
10. Massari P, Ho Y, Wetzler LM: Neisseria meningitidis
porin PorB interacts with mitochondria and protects cells
from apoptosis. Proc Natl Acad Sci U S A 2000,
97:9070-9075.
11. Muller A, Gunther D, Brinkmann V, Hurwitz R, Meyer TF, Rudel T:
Targeting of the pro-apoptotic VDAC-like porin (PorB) of
Neisseria gonorrhoeae to mitochondria of infected cells.
EMBO J 2000, 19:5332-5343.
12. Choi CH, Lee EY, Lee YC, Park TI, Kim HJ, Hyun SH, Kim SA,
Lee SK, Lee JC: Outer membrane protein 38 of Acinetobacter
baumannii localizes to the mitochondria and induces
apoptosis of epithelial cells. Cell Microbiol 2005,
7:1127-1138.
13. Galmiche A, Rassow J, Doye A, Cagnol S, Chambard JC,
Contamin S, de Thillot V, Just I, Ricci V, Solcia E et al.: The
N-terminal 34 kDa fragment of Helicobacter pylori vacuolating
cytotoxin targets mitochondria and induces cytochrome c
release. EMBO J 2000, 19:6361-6370.
14. He D, Hagen SJ, Pothoulakis C, Chen M, Medina ND, Warny M,
LaMont JT: Clostridium difficile toxin A causes early damage to
mitochondria in cultured cells. Gastroenterology 2000,
119:139-150.
15. Bantel H, Sinha B, Domschke W, Peters G, Schulze-Osthoff K,
Janicke RU: Alpha-toxin is a mediator of Staphylococcus
aureus-induced cell death and activates caspases via the
intrinsic death pathway independently of death receptor
signaling. J Cell Biol 2001, 155:637-648.
16. Petit P, Breard J, Montalescot V, El Hadj NB, Levade T, Popoff M,
Geny B: Lethal toxin from Clostridium sordellii induces
apoptotic cell death by disruption of mitochondrial
homeostasis in HL-60 cells. Cell Microbiol 2003,
5:761-771.
17. Hernandez LD, Pypaert M, Flavell RA, Galan JE: A Salmonella
protein causes macrophage cell death by inducing autophagy.
J Cell Biol 2003, 163:1123-1131.
18. Genestier AL, Michallet MC, Prevost G, Bellot G, Chalabreysse L,
Peyrol S, Thivolet F, Etienne J, Lina G, Vallette FM et al.:
Staphylococcus aureus Panton-Valentine leukocidin
directly targets mitochondria and induces Bax-independent
apoptosis of human neutrophils. J Clin Invest 2005,
115:3117-3127.
19. Matarrese P, Falzano L, Fabbri A, Gambardella L, Frank C, Geny B,
Popoff MR, Malorni W, Fiorentini C: Clostridium difficile toxin B
causes apoptosis in epithelial cells by thrilling mitochondria.
Involvement of ATP-sensitive mitochondrial potassium
channels. J Biol Chem 2007, 282:9029-9041.
20. Braun JS, Hoffmann O, Schickhaus M, Freyer D, Dagand E,
Bermpohl D, Mitchell TJ, Bechmann I, Weber JR: Pneumolysin
causes neuronal cell death through mitochondrial damage.
Infect Immun 2007, 75:4245-4254.
21. Dolezal P, Likic V, Tachezy J, Lithgow T: Evolution of the
molecular machines for protein import into mitochondria.
Science 2006, 313:314-318.
The paper reviews the current opinion on the evolution of protein import
machines found in mitochondria.
Current Opinion in Microbiology 2008, 11:9–14
14 Bacteria
22. Hoogenraad NJ, Ward LA, Ryan MT: Import and assembly of
proteins into mitochondria of mammalian cells. Biochim
Biophys Acta 2002, 1592:97-105.
23. Stojanovski D, Johnston AJ, Streimann I, Hoogenraad NJ,
Ryan MT: Import of nuclear-encoded proteins into
mitochondria. Exp Physiol 2003, 88:57-64.
24. Wiedemann N, Frazier AE, Pfanner N: The protein import
machinery of mitochondria. J Biol Chem 2004, 279:
14473-14476.
25. Neupert W, Herrmann JM: Translocation of proteins into
mitochondria. Annu Rev Biochem 2007, 76:723-749.
26. Kozjak-Pavlovic V, Ross K, Benlasfer N, Kimmig S, Karlas A,
Rudel T: Conserved roles of Sam50 and metaxins in VDAC
biogenesis. EMBO Rep 2007, 8:576-582.
27. Bos MP, Robert V, Tommassen J: Biogenesis of the gramnegative bacterial outer membrane. Annu Rev Microbiol 2007,
61:191-214.
28. Wu T, Malinverni J, Ruiz N, Kim S, Silhavy TJ, Kahne D:
Identification of a multicomponent complex required for outer
membrane biogenesis in Escherichia coli. Cell 2005, 121:
235-245.
29. Clantin B, Delattre AS, Rucktooa P, Saint N, Meli AC, Locht C,
Jacob-Dubuisson F, Villeret V: Structure of the membrane
protein FhaC: a member of the Omp85-TpsB transporter
superfamily. Science 2007, 317:957-961.
30. Bredemeier R, Schlegel T, Ertel F, Vojta A, Borissenko L,
Bohnsack MT, Groll M, von Haeseler A, Schleiff E: Functional and
phylogenetic properties of the pore-forming beta-barrel
transporters of the Omp85 family. J Biol Chem 2007,
282:1882-1890.
31. Papatheodorou P, Domanska G, Oxle M, Mathieu J, Selchow O,
Kenny B, Rassow J: The enteropathogenic Escherichia coli
(EPEC) Map effector is imported into the mitochondrial matrix
by the TOM/Hsp70 system and alters organelle morphology.
Cell Microbiol 2006, 8:677-689.
Using a genetic system, the authors demonstrate the mitochondrial
import route of the EPEC Map protein. This is one of the few studies
where import has been linked to factors of the mitochondrial protein
import machines.
Current Opinion in Microbiology 2008, 11:9–14
32. Nagai T, Abe A, Sasakawa C: Targeting of enteropathogenic
Escherichia coli EspF to host mitochondria is essential for
bacterial pathogenesis: critical role of the 16th leucine residue
in EspF. J Biol Chem 2005, 280:2998-3011.
The authors demonstrate that an EspF point mutant deficient in mitochondrial targeting prevents mitochondrial damage during infection of cell
culture models. The same mutant is attenuated in an animal model for
EPEC infection. This is the first study to demonstrate that mitochondrial
import of a bacterial protein affects pathogenicity in an in vivo animal model.
33. Muller A, Rassow J, Grimm J, Machuy N, Meyer TF, Rudel T: VDAC
and the bacterial porin PorB of Neisseria gonorrhoeae share
mitochondrial import pathways. EMBO J 2002, 21:1916-1929.
34. Malish HR, Freeman NL, Zurawski DV, Chowrashi P, Ayoob JC,
Sanger JW, Sanger JM: Potential role of the EPEC translocated
intimin receptor (Tir) in host apoptotic events. Apoptosis 2003,
8:179-190.
35. Willhite DC, Blanke SR: Helicobacter pylori vacuolating
cytotoxin enters cells, localizes to the mitochondria, and
induces mitochondrial membrane permeability changes
correlated to toxin channel activity. Cell Microbiol 2004, 6:
143-154.
36. Yamasaki E, Wada A, Kumatori A, Nakagawa I, Funao J,
Nakayama M, Hisatsune J, Kimura M, Moss J, Hirayama T:
Helicobacter pylori vacuolating cytotoxin induces activation of
the proapoptotic proteins Bax and Bak, leading to cytochrome
c release and cell death, independent of vacuolation. J Biol
Chem 2006, 281:11250-11259.
37. Lucattini R, Likic VA, Lithgow T: Bacterial proteins predisposed
for targeting to mitochondria. Mol Biol Evol 2004, 21:652-658.
38. Sisko JL, Spaeth K, Kumar Y, Valdivia RH: Multifunctional
analysis of Chlamydia-specific genes in a yeast expression
system. Mol Microbiol 2006, 60:51-66.
39. Derre I, Pypaert M, Dautry-Varsat A, Agaisse H: RNAi screen in
Drosophila cells reveals the involvement of the Tom complex
in Chlamydia infection. PLoS Pathog 2007, 3:1446-1458.
A genome-wide RNA interference screen identified 54 factors that, when
depleted, inhibit C. caviae infection. Among these factors were Tim and
Tom proteins suggesting a role for mitochondrial import in C. caviae
infection. This is the first screen that identified mitochondrial import as
crucial for bacterial infection.
www.sciencedirect.com