Proposed model of how B. abortus matures into ER-derived replicative BCVs.

(A) (a) During infection, B. abortus triggers the activation of IRE1, presumably by secreting effector molecules into the cytoplasm of host cells through a secretion system. (b) IRE1 molecules form high-order complexes at ERES with the aid of Yip1A, which are activated by autophosphorylation. (c) The activated IRE1 in turn triggers the biogenesis of ER-derived vacuoles. Atg9 and WIPI1 may be recruited to the IM at ERES, and support the formation of ER-derived vacuoles. The upregulation of the COPII components Sar1, Sec23 and Sec24 could facilitate the formation of such vacuoles. (d) The ER-derived vacuoles then fuse with endolysosomal vesicles. Given that B. abortus that have reached the ER are located in late endosomal/lysosomal compartments, they should be able to fuse with these vacuoles. (e) Once they have acquired the ER-derived membrane, BCVs retain functional features of the ER, and multiplication of B. abortus in individual vacuoles might be supported through continual accretion of ER membranes derived from the IRE1-specific UPR. (B) Knockdown of Yip1A prevents the activation of IRE1. Consequently, ER-derived membranes are not generated for bacterial replication and B. abortus remains in endosomal/lysosomal compartments. (C) Knockdown of IRE1 leads to loss of the activation of IRE1. Consequently, ER-derived membranes are not generated for bacterial replication and B. abortus remains in endosomal/lysosomal compartments.