Manipulation of the Unfolded Protein Response by Intracellular Bacterial Pathogens: Mechanisms of ER Hijacking and Therapeutic Implications

ABSTRACT The unfolded protein response (UPR) is a cellular stress response mechanism that maintains endoplasmic reticulum (ER) homeostasis through three signaling pathways mediated by IRE1α, PERK, and ATF6 sensors. While UPR's role in viral infections has been well documented, recent studies indicate that intracellular bacterial pathogens have evolved specific mechanisms to hijack UPR signaling for survival and replication. This review examines UPR manipulation strategies employed by major bacterial pathogens, including Brucella , Mycobacterium tuberculosis , Legionella , and Salmonella . These pathogens utilize effector proteins that target specific UPR components: Brucella effectors VceC, BspB, TcpB, and BspL interact with ER chaperones and ERAD machinery; M. tuberculosis proteins Rv0297, ESAT‐6, HBHA, and CdhM disrupt calcium homeostasis and alter ER morphology; Legionella Lpg0519 activates atypical ATF6 signaling; and bacterial toxins including cholera toxin bind IRE1α structural motifs for pathway activation. The molecular basis of UPR manipulation includes direct protein–protein interactions, calcium signaling interference, ER morphological disruption, and transcriptional program modulation. Bacterial hijacking of UPR pathways affects ER‐phagy processes and host immune responses, facilitating intracellular survival. UPR pathway components serve as potential targets for host‐directed therapy against persistent and drug‐resistant infections. Small molecule modulators targeting IRE1α kinase activity, PERK inhibitors, and ATF6 pathway regulators may complement conventional antimicrobial approaches. Characterization of these host‐pathogen interactions provides insights for developing therapeutic strategies that target bacterial dependencies on cellular stress responses.