The obligate intracellular bacteria Chlamydia trachomatis, the causative agent of trachoma and sexually transmitted diseases, multiply in a vacuolar compartment, the inclusion. From this niche, they secrete “effector” proteins, that modify cellular activities to enable bacterial survival and proliferation. Here, we show that the host autophagy-related protein 16-1 (ATG16L1) restricts inclusion growth and that this effect is counteracted by the secretion of the bacterial effector CT622/TaiP (translocated ATG16L1 interacting protein). ATG16L1 is mostly known for its role in the lipidation of the human homologs of ATG8 (i.e., LC3 and homologs) on double membranes during autophagy as well as on single membranes during LC3-associated phagocytosis and other LC3-lipidation events. Unexpectedly, the LC3-lipidation-related functions of ATG16L1 are not required for restricting inclusion development. We show that the carboxyl-terminal domain of TaiP exposes a mimic of an eukaryotic ATG16L1-binding motif that binds to ATG16L1’s WD40 domain. By doing so, TaiP prevents ATG16L1 interaction with the integral membrane protein TMEM59 and allows the rerouting of Rab6-positive compartments toward the inclusion. The discovery that one bacterial effector evolved to target ATG16L1’s engagement in intracellular traffic rather than in LC3 lipidation brings this “secondary” activity of ATG16L1 in full light and emphasizes its importance for maintaining host cell homeostasis.

专性细胞内细菌沙眼衣原体，沙眼和性传播疾病的病原体，在液泡室中繁殖。他们从这个小生境中分泌“效应子”蛋白，这些蛋白会修饰细胞活性以使细菌存活和繁殖。在这里，我们显示了宿主自噬相关蛋白16-1（ATG16L1）限制了包涵体的生长，并且这种效应被细菌效应物CT622 / TaiP（易位的ATG16L1相互作用蛋白）的分泌所抵消。ATG16L1因其在自噬过程中在双膜上以及在与LC3相关的吞噬作用和其他LC3脂质化事件中在单膜上ATG8的人类同源物（即LC3和同源物）的脂化作用而闻名。出乎意料的是，不需要ATG16L1的与LC3脂质相关的功能来限制包涵体的形成。我们显示，TaiP的羧基末端结构域暴露了一个真核ATG16L1结合基序的模拟物，该基序与ATG16L1的WD40域结合。这样，TaiP可以防止ATG16L1与完整的膜蛋白TMEM59相互作用，并允许Rab6阳性区室重新进入包含区。一个细菌效应子进化为以ATG16L1参与细胞内运输而不是LC3脂化为目标的发现，使ATG16L1的这种“次要”活性得以充分发挥，并强调了其对维持宿主细胞稳态的重要性。TaiP可以防止ATG16L1与完整的膜蛋白TMEM59相互作用，并允许Rab6阳性区室重新进入包涵体。一个细菌效应子进化为以ATG16L1参与细胞内运输而不是LC3脂化为目标的发现，使ATG16L1的这种“次要”活性得以充分发挥，并强调了其对维持宿主细胞稳态的重要性。TaiP阻止ATG16L1与完整的膜蛋白TMEM59相互作用，并允许Rab6阳性区室重新向包涵体转移。一个细菌效应子进化为以ATG16L1参与细胞内运输而不是LC3脂化为目标的发现，使ATG16L1的这种“次要”活性得以充分发挥，并强调了其对维持宿主细胞稳态的重要性。