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The Chlamydia Effector CT622/Taip Targets a Nonautophagy Related Function of ATG16L1

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The Chlamydia Effector CT622/Taip Targets a Nonautophagy Related Function of ATG16L1 The Chlamydia effector CT622/TaiP targets a nonautophagy related function of ATG16L1 Daniel Hamaouia, Mathilde M. Cosséa,b, Jagan Mohanc, Alf Håkon Lystadd,e, Thomas Wollertc, and Agathe Subtila,1 aUnité de Biologie cellulaire de l’infection microbienne, Institut Pasteur, UMR3691 CNRS, F-75015, Paris, France; bCollège Doctoral, Sorbonne Université, F-75005, Paris, France; cBiochimie membranaire et transport, Institut Pasteur, UMR3691 CNRS, F-75015, Paris, France; dDepartment of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, 0317 Oslo, Norway; and eCentre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0450 Oslo, Norway Edited by Ralph R. Isberg, Tufts University School of Medicine, Boston, MA, and approved September 11, 2020 (received for review March 22, 2020) The obligate intracellular bacteria Chlamydia trachomatis, the caus- phagocytosis and other LC3-lipidation events (6–9). ATG16L1 ative agent of trachoma and sexually transmitted diseases, multiply also plays an important role in the control of inflammation in a vacuolar compartment, the inclusion. From this niche, they se- through its ability to bind NOD1 and NOD2 (10). Very unex- crete “effector” proteins, that modify cellular activities to enable pectedly, we show here that the ATG16L1-driven function that is bacterial survival and proliferation. Here, we show that the host targeted by CT622 is not related to its LC3-lipidation capacity autophagy-related protein 16-1 (ATG16L1) restricts inclusion growth nor to its ability to bind NODs but to its involvement in regu- and that this effect is counteracted by the secretion of the bacterial lating intracellular traffic by interacting with the transmembrane effector CT622/TaiP (translocated ATG16L1 interacting protein). protein TMEM59. We show that CT622 inhibits the formation of ATG16L1 is mostly known for its role in the lipidation of the human the ATG16L1/TMEM59 complex, allowing the rerouting of ve- homologs of ATG8 (i.e., LC3 and homologs) on double membranes sicular traffic to the inclusion thereby rescuing inclusion growth Δ during autophagy as well as on single membranes during LC3- in the Ctr CT622 strain. associated phagocytosis and other LC3-lipidation events. Unexpect- edly, the LC3-lipidation-related functions of ATG16L1 are not re- Results quired for restricting inclusion development. We show that the CT622 Binds to ATG16L1 through Its Carboxyl-Terminal (C-Terminal) carboxyl-terminal domain of TaiP exposes a mimic of an eukaryotic CELL BIOLOGY Domain. The observation that loss of CT622 impaired inclusion ATG16L1-binding motif that binds to ATG16L1’s WD40 domain. By growth suggested that this soluble effector might contribute to doing so, TaiP prevents ATG16L1 interaction with the integral mem- the diversion of host-derived material toward the inclusion. To brane protein TMEM59 and allows the rerouting of Rab6-positive compartments toward the inclusion. The discovery that one bacte- identify the targets of CT622 in the host cytoplasm, we per- rial effector evolved to target ATG16L1’s engagement in intracellu- formed two independent pull-down (PD) experiments. We lar traffic rather than in LC3 lipidation brings this “secondary” identified 33 proteins that were significantly enriched in the activity of ATG16L1 in full light and emphasizes its importance for GST-CT622 PD fraction compared to GST, three of which being maintaining host cell homeostasis. recovered in the two independent experiments (SI Appendix, Table S1). The autophagy-related proteins ATG16L1 and ATG5 host-pathogen interactions | autophagy | ATG16L1 | intracellular traffic | were recovered in the two experiments with the highest total Chlamydia trachomatis peptide counts. To test their ability to interact with CT622, we hlamydia trachomatis is an obligate intracellular pathogen Significance Cresponsible for the most common sexually transmitted bac- terial infection (1). The bacteria reside within a vacuolar com- Some intracellular bacteria develop inside a vacuole, which partment, called the inclusion, which expands throughout the expands during the infection process. We show, here, that the developmental cycle. The host and the bacteria contribute col- protein ATG16L1 restricts the expansion of the Chlamydia lectively to the making of this compartment. In particular, host trachomatis vacuole. ATG16L1 is well known for its role in lipids are diverted to the inclusion membrane both through ve- autophagy, a process that contributes to the elimination of sicular and through nonvesicular traffic (2). The nature of the intracellular microbes. However, the restriction exerted by intercepted vesicles is not fully understood, and the presence of ATG16L1 on vacuole expansion relies on a different ATG16L1 many different Rab GTPases at the inclusion membrane suggests function. We demonstrate that the bacteria secrete an effec- that several trafficking pathways are involved (3). Key players in tor protein that prevents ATG16L1 binding to TMEM59 and allows rerouting of vesicular traffic to the vacuole. The dis- this rerouting of host-derived vesicles are the bacterial Inc pro- ’ teins, that are inserted into the inclusion membrane, and that covery that one bacterial effector evolved to target ATG16L1 s engagement in intracellular traffic emphasizes the importance interact with regulators of intracellular traffic (4). However, Inc this secondary activity of ATG16L1 for maintaining host cell proteins are confined to the inclusion membrane, which limits homeostasis. their range of action. We recently observed that the loss of ex- Δct622 pression of the soluble effector CT622 in a Ctr strain Author contributions: D.H., M.M.C., T.W., and A.S. designed research; D.H., M.M.C., J.M., resulted in several deficiencies, including a defect in inclusion A.H.L., and A.S. performed research; D.H., M.M.C., and A.S. analyzed data; and D.H. and growth, supporting the hypothesis that this soluble effector might A.S. wrote the paper. contribute to the diversion of host-derived material toward the The authors declare no competing interest. inclusion (5). In the present study, we identify the host protein This article is a PNAS Direct Submission. ATG16L1 as a target of CT622. ATG16L1 is best known for its Published under the PNAS license. role as part of the ATG12-ATG5-ATG16L1 complex, which 1To whom correspondence may be addressed. Email: [email protected]. catalyzes the lipidation of the human homologs of ATG8 This article contains supporting information online at https://www.pnas.org/lookup/suppl/ (i.e., LC3 and homologs) on double membranes during auto- doi:10.1073/pnas.2005389117/-/DCSupplemental. phagy as well as on single membranes during LC3-associated www.pnas.org/cgi/doi/10.1073/pnas.2005389117 PNAS Latest Articles | 1of11 Downloaded by guest on September 29, 2021 first performed co-immunoprecipitation (IP) experiments in cells tagged protein (CymR) expressed at similar levels as Flag-TaiP transfected with plasmids expressing Flag-CT622, GFP-ATG5, was used as a negative control. Altogether, we concluded from and/or GFP-ATG16L1. After cell lysis, we immunoprecipitated these series of experiments that ATG16L1 hinders inclusion Flag-CT622, separated the proteins by sodium dodecyl sulfate development and that one of the roles of the effector TaiP is to polyacrylamide gel electrophoresis (SDS/PAGE), and probed counteract this brake by binding to ATG16L1. Importantly, the this fraction with antibodies against the green fluorescent protein absence of ATG16L1 resulted in an approximately twofold in- Δ (GFP) by Western blot. GFP-ATG16L1 co-immunoprecipitated crease in progeny for the Ctr taiP strain (SI Appendix, Fig. S1F). with Flag-CT622 while GFP-ATG5 did not (Fig. 1A). This result This is modest compared to the 25-fold difference of infectivity Δ suggests that CT622 interacts with ATG16L1. The recovery of that exists between the Ctr taiP and the CtrWT strains (5), im- ATG5 in the PD but not in the co-IP suggests that when all plicating that while the inclusions recovered a normal size, the protein were expressed at the endogenous level, ATG5 cofrac- other phenotype associated with TaiP loss, i.e., defect of infec- tionated with CT622 via its ability to bind ATG16L1. By im- tivity of EBs, remained. This is not surprising, considering that Δ munofluorescence, we observed that coexpression of GFP- the loss of progeny in the Ctr taiP strain is largely due to the ATG16L1 with Flag-CT622 led to the relocation of Flag-CT622 formation of nonfunctional EBs (e.g., defects in TarP secretion, to GFP-ATG16L1 puncta, further supporting the hypothesis that for instance), which is likely disconnected from the defect on the the two proteins interact (SI Appendix, Fig. S1A). inclusion size. The absence of ATG16L1 did not significantly Δ CT622 exhibits a highly conserved C-terminal domain affect the progeny of the CtrWT or Ctr taiP+TaiP-Flag strains (SI (CT622Cterm) and a somewhat less conserved amino-terminal Appendix, Fig. S1F). (N-terminal) domain (CT622Nterm) (5). Co-IP experiments with each of these domains expressed individually revealed that the ATG16L1 Restricts Inclusion Growth through Its WD40 Domain. The interaction with ATG16L1 occurred via CT622Cterm (Fig. 1B). ATG16L1 N-terminal part is structurally and functionally con- To confirm this interaction in the context of an infection and in served in yeast and is responsible for its role in LC3 lipidation. Its Δ the absence
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