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Direct Targeting of Membrane Fusion by SNARE Mimicry: Convergent Evolution of Legionella Effectors

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Direct Targeting of Membrane Fusion by SNARE Mimicry: Convergent Evolution of Legionella Effectors Direct targeting of membrane fusion by SNARE mimicry: Convergent evolution of Legionella effectors Xingqi Shia,1, Partho Halderb,1, Halenur Yavuzb, Reinhard Jahnb,2, and Howard A. Shumana,2 aDepartment of Microbiology, University of Chicago, Chicago, IL 60637; and bDepartment of Neurobiology, Max Planck Institute for Biophysical Chemistry, 37077 Goettingen, Germany Contributed by Reinhard Jahn, June 8, 2016 (sent for review February 18, 2016; reviewed by Ralph R. Isberg and Josep Rizo) Legionella pneumophila, the Gram-negative pathogen causing SNARE complex (13). Whereas each intracellular fusion step Legionnaires’ disease, infects host cells by hijacking endocytic path- appears to involve its own specific set of SNARE proteins, SNAREs ways and forming a Legionella-containing vacuole (LCV) in which the on their own are rather promiscuous, with members of the same bacteria replicate. To promote LCV expansion and prevent lysosomal subfamily being capable of substituting for each other in cells, and targeting, effector proteins are translocated into the host cell where even more so in vitro (12). they alter membrane traffic. Here we show that three of these effec- Although the function of most Legionella effectors is still un- tors [LegC2 (Legionella eukaryotic-like gene C2)/YlfB (yeast lethal factor known, several of them were shown to target trafficking protein, B),LegC3,andLegC7/YlfA]functionally mimic glutamine (Q)-SNARE including small GTPases such as Rab1 and Arfs, or to interfere proteins. In infected cells, the three proteins selectively form complexes with the formation of autophagosomes (14). Moreover, LCV for- with the endosomal arginine (R)-SNARE vesicle-associated membrane mation is associated with the formation of noncognate SNARE protein 4 (VAMP4). When reconstituted in proteoliposomes, these pro- complexes between an R-SNARE functioning in trafficking be- teins avidly fuse with liposomes containing VAMP4, resulting in a tween the ER and the Golgi apparatus (mSec22b) and glutamine stable complex with properties resembling canonical SNARE com- (Q)-SNAREs normally operating at the plasma membrane [syn- plexes. Intriguingly, however, the LegC/SNARE hybrid complex can- taxins 2, 3, 4, and synapotosomal-associated protein (SNAP)-23] not be disassembled by N-ethylmaleimide-sensitive factor. We (15). Complex formation appears to be enhanced by DrrA, a conclude that LegCs use SNARE mimicry to divert VAMP4-containing vesicles for fusion with the LCV, thus promoting its expansion. In Legionella effector that binds to the SNARE Syntaxin 3, a reaction MICROBIOLOGY addition, the LegC/VAMP4 complex avoids the host’s disassembly that appears to be regulated by the small GTPase Rab1 (16). machinery, thus effectively trapping VAMP4 in an inactive state. Intriguingly, some effectors bear superficial similarity to SNAREs and thus may interfere with SNARE function. For example, the Legionella pneumophila | SNAREs | NSF | membrane fusion IncA effector of Chlamydia, was shown to interfere with SNARE assembly (17, 18). More recently, another putative Legionella SNARE paralog was identified by bioinformatic searches (LseA) egionnaires’ disease in humans is caused by Legionella pneu- andshowntointeractwithhostcellSNAREs(19). mophila (1), which enters human monocytes and alveolar mac- L In this study, we have investigated whether three structurally rophages by macropinocytosis. After endocytotic uptake, Legionella related Legionella effectors (LegC2/YlfB, LegC3, and LegC7/ prevents fusion with lysosomes to escape host degradation and establishes a replication niche, called the Legionella-containing YlfA) (20) interact with mammalian SNAREs, and if so, whether vacuole (LCV) (2). To achieve these goals, Legionella translocates this interaction affects SNARE function. These LegC-proteins effector proteins through a type IVB (Icm/Dot) secretion system into the host cytoplasm or into the LCV membrane (2–5). Around Significance 300 Legionella effectors were identified by genetic or bioinformatic approaches (6–8). Whereas growth and survival of Legionella de- Legionella pneumophila, the bacterium causing Legionnaires’ pends on these effector proteins, they appear to be highly redundant disease, invades lung cells by creating intracellular vacuoles because as many as 71 effector-encoding genes can be deleted in a where it is protected and where it can multiply. For expansion, single strain that retains the ability to grow in macrophages (9). the vacuoles must hijack intracellular vesicles while avoiding For membrane expansion, LCVs recruit trafficking vesicles from destruction by lysosomes. To achieve these goals, Legionella the host cell. Mainly, these vesicles originate from trafficking exports effector proteins into the cytoplasm and into the mem- vesicles shuttling between the endoplasmic reticulum (ER) and the brane of the vacuole. Here we report that certain Legionella ef- cis-face of the Golgi apparatus (10), although other sources of fectors mimic intracellular fusion proteins of the SNARE family, membrane, e.g., of endosomal sources, cannot be excluded (11). allowing them to selectively fuse with specific intracellular Thus, Legionella is capable of redirecting trafficking vesicles to fuse transport vesicles, thus providing more space for the dividing with the LCV, but the mechanisms by which this is achieved are bacteria. In contrast to SNAREs, however, the Legionella proteins only slowly emerging. In eukaryotes, the specificity of membrane can be used only once, thus allowing the bacteria to control the traffic is governed by sets of regulatory proteins, which ultimately amount of hijacked vesicles. converge to regulate vesicle fusion carried out by SNARE [soluble Author contributions: X.S., P.H., R.J., and H.A.S. designed research; X.S., P.H., H.Y., and H.A.S. N-ethylmaleimide-sensitive factor (NSF) attachment protein re- performed research; X.S., P.H., R.J., and H.A.S. analyzed data; and X.S., P.H., R.J., and H.A.S. ceptor] proteins. The regulatory proteins include small GTPases of wrote the paper. the Rab and Arf families. These proteins operate as molecular Reviewers: R.R.I., Howard Hughes Medical Institute/Tufts University School of Medicine; switches that, once activated, recruit effector proteins from the and J.R., University of Texas Southwestern Medical Center. cytoplasm to ensure fusion with the correct target by controlling The authors declare no conflict of interest. SNAREs. SNAREs comprise a family of small and mostly mem- Freely available online through the PNAS open access option. brane-anchored proteins (12). They are characterized by coiled-coil 1X.S. and P.H. contributed equally to this work. – (CC) forming SNARE motifs that assemble between the mem- 2To whom correspondence may be addressed. Email: [email protected] or hashuman@ branes and thus initiate fusion. SNARE motifs are classified into uchicago.edu. four subfamilies termed Qa-, Qb-, Qc-, and arginine (R)-SNAREs, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. with one of each required for assembly of a fusion-competent 1073/pnas.1608755113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1608755113 PNAS Early Edition | 1of6 Downloaded by guest on September 23, 2021 comprise a group of transmembrane proteins that possess coiled- (22). Hence, we investigated whether the Legionella effector coil motifs reminiscent of SNARE proteins, raising the possi- proteins LegC2/YlfB, LegC3, and LegC7/YlfA interact with host bility that they may form hybrid complexes with endogenous cell SNAREs to modulate membrane fusion. To examine whether SNARE proteins. Indeed, LegC3 was shown previously to inhibit LegC proteins interact with host cell R-SNAREs, we infected SNARE-mediated homotypic fusion of yeast vacuoles in vitro, phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 but a direct interaction between LegC3 and SNAREs was not macrophage-like cells with Legionella strains overexpressing either observed (21). We found that all three LegC proteins selectively β-lactamase (TEM) or N-terminally TEM-tagged versions of one interact with the R-SNARE vesicle-associated membrane protein of each of the effector proteins LegC2, LegC3, or LegC7. Six 4 (VAMP4), and furthermore, that the availability of VAMP4 is hours after infection, LegC proteins were immunoprecipitated rate limiting for the intracellular proliferation of Legionella.Using from cell lysates using anti-TEM antibodies. Immunoblotting for in vitro fusion assays, we also report that the three LegC pro- TEM revealed bands of the expected size in all three cases both in teins together are capable of substituting for the endogenous the lysates and immunoprecipitates [TEM (30 kDa), TEM-LegC2 Q-SNARE partners of VAMP4, resulting in the formation of hybrid (76 kDa), TEM-LegC3 (93 kDa), and TEM-LegC7 (78 kDa)]. We LegC/SNARE complexes and fusion with an efficiency comparable then examined the precipitated material for the presence of to that observed with the endogenous SNARE partners of VAMP4. mammalian R-SNAREs including VAMP2/Synaptobrevin and Intriguingly, the hybrid LegC/VAMP4 complex formed during fu- VAMP3/Cellubrevin (exocytosis) (23), VAMP4 (trans-Golgi net- sion cannot be dissociated by the SNARE disassembly enzyme NSF. work) (24), VAMP8 (late endosome/lysosome), as well as Sec22b and Ykt6 (ER–Golgi transport) (25). Whereas all six R-SNARE Results proteins were clearly detectable in the lysate, VAMP4 was the only LegC2, LegC3, and LegC7 Resemble Mammalian Q-SNAREs and
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