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NEWS & VIEWS doi:10.

1038/nature24157

MIC RO B IO LO GY cells infected with S.flexneri were completely


devoid of hGBP1, whereas galectin-3 was

Bacteria disarm still present, suggesting that hGBP1 had been


selectively degraded. Other bacteria that can
also enter the epithelial-cell cytoplasm, such as

host-defence proteins
Listeria monocytogenes and Salmonella enter-
ica Typhimurium, did not degrade hGBP1;
instead, they were quickly surrounded by it.
Such action could kill the bacteria by breaking
Infection with Shigella flexneri bacteria is a major cause of infant death. It emerges down the microbial cell wall9,10 or by recruiting
that S. flexneri evades intracellular defences by releasing a protein that triggers other antibacterial proteins2,7,11.
the destruction of members of a key family of host enzymes. The authors next investigated why hGBP1
disappeared from cells upon infection with
S.flexneri. One mechanism for targeting
JOHN D. MACMICKING called IcsB that helps it to evade autophagic intracellular protein destruction is a pathway
destruction6. GBPs can interact with auto in which a ubiquitin-protein tag is added to a

P
athogenic microbes that invade a human phagic proteins that might target bacteria for protein in a process called ubiquitination. The
host must overcome many obstacles to destruction2,3,710. This raises the possibility addition of many ubiquitin tags marks the
establish infection. One of the first is an that GBPs also target S.flexneri, and, if this is protein for destruction in a multi-protein
immune response known as cell-autonomous so, poses the question of whether the bacterium complex called the proteasome. When the
defence, which occurs in a cell under patho- has evolved a counterpunch. authors treated cells with a proteasomal inhibi-
genic attack1. This form of innate defence To investigate whether S.flexneri combats tor or with an inhibitor that blocks a type of
operates in most human cells, and signalling GBPs, Li and colleagues used a fluorescent tag enzyme, known as an E1 ubiquitin ligase,
from immune-system proteins, including to monitor the recruitment of human GBP1 that acts in the first step of ubiquitination, it
those of the interferon family, helps to mobi- (hGBP1) protein to bacteria in the host-cell prevented hGBP1 loss on S. flexneri infection.
lize it2. Interferons rally hundreds of other cytoplasm. They also tracked the galectin-3 To determine how S. flexneri achieves
proteins into action, including a group of protein, which enabled them to identify proteasomal-mediated GBP destruction, Li
enzymes called guanylate-binding proteins damaged vacuoles from which the bacterium and colleagues tested about 13,000 strains of
(GBPs), which have potent antimicrobial had escaped. S.flexneri that had mutant versions of dif-
activity against a range of intracellular patho- What they found was unexpected. Epithelial ferent genes. One strain that was unable to
gens2,3. Whether pathogens promote successful
infection by disarming GBPs has been a key
unanswered question. In a paper online in
Nature, Li etal.4 report that the answer is yes.
The bacterium Shigella flexneri causes a
Shigella
gut infection called shigellosis, also known as flexneri
Epithelial-cell membrane
bacillary dysentery, which is associated with
symptoms including diarrhoea. More than Cytoplasm
160million cases of shigellosis are estimated
to occur globally each year, resulting in some
Proteasome
600,000deaths, mostly in children less than Ub
Ub Ub
5years old in developing countries5. Infec- IpaH9.8 GBP
tion occurs when ingestion of faecally con-
taminated food or water enables S.flexneri to
invade epithelial cells of the intestine, causing
severe inflammation and disrupting the guts Bacterial
proteins
cellular integrity. GBP
When S. flexneri enters a host cell (Fig.1), degradation
it is initially trapped inside a membrane-
bound compartment called a vacuole, which Vacuole
it disrupts to escape into the cytoplasm6. The Prevention of GBP-mediated
defence response
bacterium then encounters defence responses
that can destroy or disable it, for example
through an intracellular degradation path- Figure 1 | A bacterial protein triggers destruction of host proteins involved in immune defence.
way called autophagy1,2. However, invading Li etal.4 investigated how the bacterial pathogen Shigella flexneri escapes host defences when it infects
bacteria can transfer proteins directly into human epithelial cells. When the bacterium enters the cell, it is initially enclosed in a membrane-bound
compartment called a vacuole. The bacterium disrupts this membrane and enters the cytoplasm, where
their hosts cytoplasm through a needle-like
it releases proteins to establish infection. One of these is IpaH9.8, which is an enzyme known as an E3
structure called the type III secretion system6, ubiquitin ligase. The authors showed that IpaH9.8 binds host enzymes called guanylate-binding proteins
helping it to combat the immune response (GBPs), which are needed for intracellular defence, revealing that this type of key defence protein is
and promote bacterial replication and spread. directly targeted by a bacterial protein. IpaH9.8 adds ubiquitin-protein (Ub) tags to GBPs, marking them
Shigella flexneri transfers more than a dozen for degradation by a host-cell multi-protein complex called the proteasome. This enables the bacteria to
such bacterial proteins, including one avoid the action of GBPs, which may destroy some types of bacterium by targeting their cell wall9,10.

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RESEARCH NEWS & VIEWS

destroy hGBP1 had a disrupted version of the activation of a host multi-protein complex questions. Determining why IpaH9.8 targets
ipaH9.8 gene. This gene encodes an enzyme called the inflammasome, which can sense some GBPs and not others might require struc-
known as an E3ubiquitin ligase (IpaH9.8), microbial products released by bacterial tural studies that could also provide results
which aids the process leading to the final step destruction3,810 and enlists GBPs in the assem- with implications for antibiotic drug design.
of ubiquitin tagging for proteasomal destruc- bly of specific inflammasome complexes3,11,12 With the identification of the complete GBP
tion of a protein. The authors demonstrated that trigger a systemic immune response family and other closely related immune-
that IpaH9.8 could add ubiquitin tags to beyond the infected cell. Shigellaflexneri there- system enzymes several years ago3,7,11, an
certain lysine amino-acid residues of hGBP1 fore targets a chink in its hosts armour that exciting chapter in hostpathogen biology has
in cells grown invitro. The ipaH9.8 gene lies potentially allows it to disable several defences begun. Expect more plot twists and intriguing
in a region of the genome harbouring genes in one fell swoop. characters as this fascinating story of intra
that form components released by the type III The authors investigated the invivo function cellular skirmishes during infection continues
secretion system, suggesting that the protein of IpaH9.8. Mice exposed to S.flexneri that to unfold.
encoded by ipaH9.8 is directly delivered into express IpaH9.8 rapidly succumbed to infec-
the host cytoplasm on infection. tion, whereas animals given S.flexneri that John D. MacMicking is at the Howard
Shigella flexneri contains a small family of lacked IpaH9.8 survived. However, mice Hughes Medical Institute and the Systems
IpaH E3 ubiquitin ligases6, but the other IpaH that lacked five members of the GBP family Biology Institute, Yale University,
family members tested by the authors did not died when infected with the S.flexneri miss- West Haven, Connecticut 06477, USA, and
degrade hGBP1. Moreover, Li and colleagues ing IpaH9.8, because the removal of the host in the Departments of Microbial Pathogenesis
demonstrated that if they engineered S.Typhi defence provided by these GBPs enabled the and Immunobiology, Yale University School of
murium to express ipaH9.8, this sufficed for S.flexneri mutant to now cause infection. Medicine.
the bacterium to gain the capacity to destroy Together, these results demonstrate that e-mail: john.macmicking@yale.edu
hGBP1 in human cells. IpaH9.8 is needed for bacteria to specifically
1. Randow, F., MacMicking, J. D. & James, L. C. Science
Notably, when the authors conducted evade a GBP-mediated immune response. 340, 701706 (2013).
invitro tests (in which they also provided the This result highlights the co-evolutionary 2. MacMicking, J. D. Nature Rev. Immunol. 12,
E1 and E2 needed for ubiquitination), they battle between host defence proteins and 367382 (2012).
found that IpaH9.8 enabled the ubiquitination bacterial proteins to gain ascendancy during 3. Kim, B.-H. et al. Nature Immunol. 17, 481489
(2016).
of more than half of all the GBP family mem- infection. Indeed, a rapidly expanding reper- 4. Li, P. et al. Nature http://dx.doi.org/10.1038/
bers found in humans and mice (which have toire of host proteins targeted by bacterial E3 nature24467 (2017).
7 and 11, respectively)3,7,11. Hence, IpaH9.8 ubiquitin ligases has been identified. These 5. Kotloff, K. L. et al. Bull. World Health Organ. 77,
651666 (1999).
could enable S.flexneri to degrade many GBPs include: NF-kB, which is part of a key immune 6. Ogawa, M., Handa, Y., Ashida, H., Suzuki, M. &
that often act in concert to restrict bacterial signalling pathway; autophagic proteins; and Sasakawa, C. Nature Rev. Microbiol. 6, 1116
replication3,711. Yet microbial interference proteins that contribute to an inflammation- (2008).
with this enzyme family has not been observed triggered cell-death process13. GBPs now join 7. Kim, B.-H. et al. Science 332, 717721 (2011).
8. Meunier, E. et al. Nature 509, 366370 (2014).
previously for any bacterial pathogen. that list. 9. Man, S. M. et al. Nature Immunol. 16, 467475
GBP ubiquitination by IpaH9.8 occurred Li and colleagues discovery of a microbial (2015).
independently of GBP activation, which is strategy that disarms GBPs provides a major 10. Meunier, E. et al. Nature Immunol. 16, 476484
needed for the enzymes to target bacteria conceptual advance that is reinforced by a (2015).
11. Kim, B. H., Shenoy, A. R., Kumar, P., Bradfield, C. J.
after infection3,7,11. This suggests that IpaH9.8 similar study just published14. Both reports & MacMicking, J. D. Cell Host Microbe 12, 432444
can engage GBPs before they act to restrict highlight the increasing importance of this (2012).
microbial growth. Such early intervention group of enzymes in intracellular immune 12. Shenoy, A. R. et al. Science 336, 481485 (2012).
13. Ashida, H. & Sasakawa, C. Curr. Opin. Microbiol. 35,
would block not only GBP-dependent bacter defences. How GBPs initially recognize bac- 1622 (2017).
ial destruction through enzyme-mediated teria in the cytoplasm, and how they drive 14. Wandel, M. P. et al. Cell Host Microbe 22, 507518
changes to the bacterial cell wall, but also bacterial destruction, are key unanswered (2017).

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